Anti-viral compounds

ABSTRACT

Compounds effective in inhibiting replication of Hepatitis C virus (“HCV”) are described. This invention also relates to processes of making such compounds, compositions comprising such compounds, and methods of using such compounds to treat HCV infection.

This application claims the benefit from and incorporates herein byreferences the entire content of U.S. application Ser. No. 12/644,432,filed Dec. 22, 2009; which claims priority to U.S. ProvisionalApplication No. 61/140,318, filed Dec. 23, 2008.

FIELD

The present invention relates to compounds effective in inhibitingreplication of Hepatitis C virus (“HCV”). The present invention alsorelates to compositions comprising these compounds and methods of usingthese compounds to treat HCV infection.

BACKGROUND

HCV is an RNA virus belonging to the Hepacivirus genus in the Flaviridaefamily. HCV has enveloped virions that contain a positive stranded RNAgenome encoding all known virus-specific proteins in one single,uninterrupted, open reading frame. The open reading frame comprisesapproximately 9500 nucleotides encoding a single large polyprotein ofabout 3000 amino acids. The polyprotein comprises a core protein,envelope proteins E1 and E2, a membrane bound protein p7, and thenon-structural proteins NS2, NS3, NS4A, NS4B, NS5A and NS5B.

HCV infection is associated with progressive liver pathology, includingcirrhosis and hepatocellular carcinoma. Chronic hepatitis C may betreated with peginterferon-alpha in combination wish ribavirin.Substantial limitations to efficacy and tolerability remain as manyusers suffer from side effects and viral elimination from the body isoften inadequate. Therefore, there is a need for new drugs to treat HCVinfection.

SUMMARY

The present invention features compounds of Formulae I, II and III, andpharmaceutically acceptable salts thereof. These compounds and salts arecapable of inhibiting the replication or HCV.

The present invention also features compositions comprising thecompounds or salts of the present invention. The compositions can alsoinclude other therapeutic agents, such as HCV helicase inhibitors, HCVpolymerase inhibitors, HCV protease inhibitors, NS5A inhibitors, CD81inhibitors, cyclophilin inhibitors, or internal ribosome entry site(IRES) inhibitors.

The present invention further features methods of using the compounds orsalts of the present invention to inhibit HCV replication. The methodscomprise contacting cells infected with HCV virus with a compound orsalt of the present invention, thereby inhibiting the replication of HCVvirus in the cells.

In addition, the present invention features methods of using thecompounds or salts of the present invention, or compositions comprisingthe same, to treat HCV infection. The methods comprise administering acompound or salt of the present invention, or a pharmaceuticalcomposition comprising the same, to a patient in need thereof, therebyreducing the blood or tissue level of HCV virus in the patient.

The-present invention also features use of the compounds or salts of thepresent invention for the manufacture of medicaments for the treatmentof HCV infection,

Furthermore, the present invention features processes of making thecompounds or salts of the invention.

Other features, objects, and advantages of the present invention areapparent in the detailed description that follows. It should beunderstood, however, that the detailed description, while indicatingpreferred embodiments of the invention, are given by way of illustrationonly, not limitation. Various changes and modifications within the scopeof the invention will become apparent to those skilled in the art fromthe detailed description.

DETAILED DESCRIPTION

The present invention features compounds having Formula I, andpharmaceutically acceptable salts thereof.

wherein:

-   -   A₁ is C₅-C₁₀carbocyclyl or 5- to 10-membered heterocyclyl, and        is substituted with —X₁—R₇, wherein said C₅-C₁₀carbocycyl and 5-        to 10-membered heterocyclyl are optionally substituted with one        or more R_(A);    -   A₂ is C₅-C₁₀carbocyclyl or 5- to 10-membered heterocyclyl, and        is substituted with —X₂—R₈, wherein said C₅-C₁₀carbocyclyl and        5- to 10-membered heterocyclyl are optionally substituted with        one or more R_(A);    -   X₁ and X₂ are each independently selected from a bond, —L_(S)—,        —O—, —S—, or —N(R_(B))—;    -   R₇ and R₈ are each independently selected from hydrogen, —L_(A),        C₅-C₁₀carbocyclyl, or 5- to 10-membered heterocyclyl, wherein at        each occurrence said C₅-C₁₀carbocyclyl and 5- to 10-membered        heterocycyl are each independently optionally substituted with        one or more R_(A);    -   Z₁ and Z₂ are each independently selected from a bond,        —C(R_(C)R_(C′))—, —O—, —S—, or —N(R_(B))—;    -   W₁, W₂, W₃, and W₄ are each independently selected from N or        C(R_(D)), wherein R_(D) is independently selected as each        occurrence from hydrogen or R_(A);    -   R₁ and R₂ are each independently selected from hydrogen or        R_(A);    -   R₃ and R₄ are each independently selected from hydrogen or        R_(A); or R₃ and R₄, taken together with the carbon atoms to        which they are attached, form a C₅-C₁₀carbocyclic or 5- to        10-membered heterocyclic ring, wherein said C₅-C₁₀carbocyclic        and 5- to 10-membered heterocyclic ring are optionally        substituted with one or more R_(A);    -   R₅ and R₆ are each independently selected from hydrogen or        R_(A); or R₅ and R₆, taken together with the carbon atoms to        which they are attached, form a C₅-C₁₀carbocyclic or 5- to        10-membered heterocyclic ring, wherein said C₅-C₁₀carbocyclic        and 5- to 10-membered heterocyclic ring are optionally        substituted with one or more R₆;    -   T is selected from a bond, —L_(S)—, —L_(S)—M—L_(S)—,        —L_(S)—M—L_(S)—M′—L_(S)—, wherein M and M′ are each        independently selected from a bond, —O—, —S—, —N(R_(B))—,        —C(O)—, —S(O)₂—, —S(O)—, —OS(O)—, —OS(O)₂—, —S(O)₂O—, —S(O)O—,        —C(O)O—, —OC(O)—, —OC(O)O—, —C(O)N(R_(B))—, —N(R_(B))C(O)—,        —N(R_(B))C(O)O—, —OC(O)N(R_(B))—, —N(R_(B))S(O)—,        —N(R_(B))S(O)₂—, —S(O)N(R_(B))—, —S(O)₂N(R_(B))—,        —C(O)N(R_(B))C(O)—, —N(R_(B))C(O)N(R_(B′))—,        —N(R_(B))SO₂N(R_(B′))—, —N(R_(B))S(O)N(R_(B′))—,        C₅-C₁₀carbocycle, or 5- to 10-membered heterocycle, and wherein        T is optionally substituted with one or more R_(A);    -   R_(A) is independently selected at each occurrence from halogen,        hydroxy, mercapto, amino, carboxy, nitro, phosphate, oxo,        thioxo, formyl, cyano, —L_(A), or —L_(S)—R_(E);    -   R_(B) and R_(B′) are each independently selected at each        occurrence from hydrogen; or C₂-C₆alkyl, C₂-C₆alkenyl,        C₂-C₆alkynyl, C₃-C₆carbocyclyl, C₃-C₆carbocyclylC₁-C₆alkyl, 3-        to 6-membered heterocyclyl, or (3- or 6-membered        heterocyclyl)C₁-C₆alkyl, each of which is independently        optionally substituted at each occurrence with one or more        substituents selected from halogen, hydroxy, mercapto, amino,        carboxy, nitro, phosphate, oxo, thioxo, formyl or cyano;

R_(C) and R_(C′) are each independently selected at each occurrence fromhydrogen; halogen; hydroxy; mercapto; amino; carboxy; nitro; phosphate;oxo; thioxo; formyl; cyano; or C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,or C₃-C₆carbocyclyl, each of which is independently optionallysubstituted at each occurrence with one or more substituents selectedfrom halogen, hydroxy, mercapto, amino, carboxy, nitro, phosphate, oxo,thioxo, formyl or cyano;

-   -   L_(A) is independently selected at each occurrence from        C₁-C₆alkyl, C₂-C₆alkenyl, or C₂-C₆alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —O—R_(S), —S—R_(S),        —N(R_(S)R_(S′)), —OC(O)R_(S), —C(O)OR_(S), nitro, phosphate,        oxo, thioxo, formyl or cyano;    -   L₅, L_(5′) and L_(5″) are each independently selected at each        occurrence from a bond; or C₁-C₆alkylene, C₂-C₆alkenylene, or        C₂-C₆alkynylene, each of which is independently optionally        substituted at each occurrence with one or more substituents        selected from halogen, —O—R_(S), —S—R_(S), —N(R_(S)R_(S′)),        —OC(O)R_(S), —C(O)OR_(S), nitro, phosphate, oxo, thioxo, formyl        or cyano;    -   R_(E) is independently selected at each occurrence from        —O—R_(S), —S—R_(S), —C(O)R_(S), —OC(O)R_(S″)),        —N(R_(S))C(O)N(R_(S′)R_(S″)), —OS(O)—R_(S), —OS(O)₂—R_(S),        —S(O)₂OR_(S), —S(O)OR_(S), —OC(O)OR_(S), —N(R_(S))C(O)OR_(S′),        —OC(O)N(R_(S)R_(S′)), —N(R_(S))S(O)—R_(S″, —S(O)N(R)        _(S)R_(S′)), —C(O)N(R_(S))C(O)—R_(S′, C) ₃-C₆carbocyclyl, or 3-        to 6-membered heterocyclyl, and said C₃-C₆carbocyclyl and 3- to        6-membered heterocyclyl are each independently optionally        substituted at each occurrence with one or more substituents        selected from C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, R_(S)        (except hydrogen), halogen, —O—R_(B), —S—R_(B), —N(R_(B)R_(B′)),        —OC(O)R_(B), —C(O)OR_(B), nitro, phosphate, oxo, thioxo, formyl        or cyano; and    -   R_(S), R_(S′) and R_(S″) are each independently selected at each        occurrence from hydrogen; or C₁-C₆alkyl, C₂-C₆alkenyl,        C₂-C₆alkynyl, C₃-C₆carbocyclyl, C₃-C₆carbocyclylC₁-C₆alkyl, 3-        to 6-membered heterocyclyl, or (3- to 6-membered        heterocyclyl)C₁-C₆alkyl, each of which is independently        optionally substituted at each occurrence with one or more        substituents selected from halogen, —O—R_(B), —S—R_(B),        —N(R_(B)R_(B′)), —OC(O)R_(B), —C(O)OR_(B), nitro, phosphate,        oxo, thioxo, formyl or cyano.

A₁ and A₂ are preferably independently selected from C₅-C₆carbocycles or5- to 6-membered heterocycles (e.g., phenyl, thiazolyl, thienyl,pyrrolidinyl or piperidinyl), and are each independently optionallysubstituted with one or more R_(A). A₁ and A₂ are substituted with—X₁—R₇ and —X₂—R_(S), respectively. The ring system in A₁ can beidentified to, or different from, that in A₂. For instance, A₁ and A₂can both be phenyl, or one is phenyl and the other is thiazolyl. Z₁ andT can be attached to A₁ via any two substitutable ring atoms on A₁, andZ₂ and T can be attached to A₂ via any two substitutable ring atoms onA₂. Two adjacent R_(A) on A₁ (or A₂), taken together with the ring atomsto which they are attached, may form a C₅-C₆carbocycle or a 5- to6-membered heterocycle.

Preferably, R₃ and R₄, taken together with the carbon atoms to whichthey are attached, form a C₅-C₆carbocycle or a 5- to 6-memberedheterocycle, which is optionally substituted with one or more R_(A).Non-limiting examples of suitable 5- to 6-membered carbocycles orheterocycles include

where W₅ and W₆ are independently N or C(R_(D)), Q is N or C(R_(D)), andR_(D), R₉ and R₁₁ are each independently selected from hydrogen orR_(A). Preferred examples of suitable 5- to 6-membered heterocyclesinclude

where R₉, R₁₀, and R₁₁ are each independently selected from hydrogen orR_(A).

Preferably, R₅ and R₆ taken together with the carbon atoms to which theyare attached, also form a C₅-C₆carbocycle or a 5- to 6-memberedheterocyclic which is optionally substituted with one or more R_(A).Non-limiting examples of suitable 5- to 6-membered carbocycles orheterocycles include

where W₇ and W₈ are each independently N or C(R_(D)), Q is N orC(R_(D)), and R_(D), R₁₂ and R₁₄ are each independently selected fromhydrogen or R_(A). Preferred examples of suitable 5- to 6-memberedheterocycles include

where R₁₂, R₁₃, and R₁₄ are each independently selected from hydrogen orR_(A).

More preferably, R₃ and R₄, taken together with the carbon atoms towhich they are attached, form

and R₅ and R₆, taken together with the carbon atoms to which they areattached, form

where R₉, R₁₀, R₁₁, R₁₂, R₁₃, and R₁₄ are each independently selectedfrom hydrogen or R_(A). Preferably, R₉, R₁₀, R₁₁, R₁₂, R₁₃, and R₁₄ areeach independently selected from hydrogen; halogen; or C₃-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆carbocyclyl, orC₃-C₆carbocyclyC₃-C₆alkyl, each of which is independently optionallysubstituted al each occurrence with one or more substituents selectedfrom halogen, hydroxy, mercapto, amino, carboxy, nitro, phosphates, oxo,thioxo, formyl or cyano. Highly preferably, R₉ and R₁₂ are eachindependently selected from C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₃-C₆carbocyclyl (e.g., C₃-C₆cycloalkyl), or C₃-C₆carbocyclyC₁-C₆alkyl(e.g., C₃-C₆cycloalkylC₁-C₆alkyl), each of which is independentlyoptionally substituted at each occurrence with one or more substituentsselected from halogen, hydroxy, mercapto, amino, carboxy, nitro,phosphate, oxo, thioxo, formyl or cyano; and R₁₀, R₁₁, R₁₃ and R₁₄ arehydrogen.

R₇ and R₈ are preferably independently selected from C₅-C₆carbocycles or5- to 6-membered heterocycles, and are each independently optionallysubstituted with one or more R_(A). The ring system in R₇ can beidentical to, or different from, that in R₈. More preferably, both R₇and R₈ are phenyl, and are each independently optionally substitutedwith one or more R_(A) (e.g., —N(R_(S)R_(S′)), such as —NH₂).

X₁ and X₂ are preferably independently selected from —CH₂—, —O—, or —S—.

Z₁ and Z₂ are preferably independently —N(R_(B))—, such as —NH— or—N(C₁-C₆alkyl)—,

T can be selected, without limitation, from the following moieties:

where k is 1 or 2, R and R* are independently hydrogen or C₁-C₆alkyl,and R′ and R″ are independently

Preferably, T is selected from Table 4 described below.

More preferably, T is —L_(S)—N(R_(T))—L_(S)—(e.g., —CH₂—N(R_(T))—CH₂—),or L_(S)—C(R_(T)R_(T)′)—L_(S)—(e.g., —CH₂—C(R_(T)R_(T)′)—CH₂—), R_(T) isC₁-C₆alkyl, C₂-C₆alkenyl, or C₂-C₆alkynyl, each of which isindependently optionally substituted at each occurrence with one or moresubstituents selected from halogen, —O—R_(S), —S—R_(S), —N(R_(S)R_(S′)),—OC(O)R_(S), —C(O)OR_(S), nitro, phosphate, oxo, thioxo, formyl orcyano; or R_(T) is C₃-C₆carbocyclyl, C₃-C₆carbocyclylC₁-C₆alkyl, 3- to6-membered heterocyclyl, or (3- or 6-membered heterocyclyl)C₁-C₆alkyl,each of which is independently optionally substituted at each occurrencewith one or more substituents selected from C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, R_(S) (except hydrogen), halogen, —O—R_(B), —S—R_(B),—N(R_(B)R_(B′)), —OC(O)R_(B), —C(O)OR_(B), nitro, phosphate, oxo,thioxo, formyl or cyano. R_(T′60) is R_(A), and preferably R_(T′) ishydrogen. L_(S), L_(S′), R_(A), R_(B), R_(b′), R_(S), and R_(S′) are asdefined above.

In one embodiment, A₁ is a 5- to 6-membered carbocycle or heterocycle(e.g., phenyl, thiazolyl, thienyl, pyrrolidinyl or piperidinyl), whichis substituted with —X₁—R₇ and is optionally substituted with one ormore R_(A), and A₂ is a 5- to 6-membered carbocycle or heterocycle(e.g., phenyl, thiazolyl, thienyl, pyrrolidinyl or piperidinyl), whichis substituted with —X₂—R_(S) and is optionally substituted with one ormore R_(A), R₃ and R₄, taken together with the carbon atoms to whichthey are attached, form a 5- to 6-membered carbocycle or heterocyclewhich is optionally substituted with one or more R_(A). R_(5 l and R) ₆,taken together with the carbon atoms to which they are attached, alsoform a 5- to 6-membered carbocycle or heterocycle which is optionallysubstituted with one or more R_(A). Preferably, both A₁ and A₂ arephenyl, and are substituted with —X₁—R₇ and —X₂—R₈, respectively, whereX₁ and X₂ preferably are independently selected from —CH₂—, —O—, or —S—,and R₇ and R₈ preferably are phenyl and are each independentlyoptionally substituted with one or more R_(A).

In another embodiment, at least one of R₇ and R₈ is a 5- to 6-memberedcarbocycle or heterocycle (e.g., phenyl), which is optionallysubstituted with one or more R_(A). In still another embodiment, R₇ andR₈ are each independently selected from 5- to 6-membered carbocycles orheterocycles, and are each independently optionally substituted with oneor more R_(A).

In a further embodiment, W₁, W₂, W₃ and W₄ are N, and Z₁ and Z₂ areindependently —N(R_(B))—. Preferably, Z₁ and Z₂ are independentlyselected from —NH—, —N(C₁-C₆alkyl)—, —N(C₂-C₆alkenyl)—,—N(C₂-C₆alkynyl)—, —N(C₁-C₆haloalkyl)—, —N(C₂-C₆haloalkenyl)—, or—N(C₂-C₆haloalkynyl)—. More preferably, Z₁ and Z₂ are independentlyselected from —NH— or —N(C₁-C₆alkyl)—.

In still another embodiment, R₃ and R₄, taken together with the carbonatoms to which they are attached, form

R₅ and R₆, taken together with the carbon atoms to which they areattached, form

R₉, R₁₀, R₁₁, R₁₂, R₁₃, and R₁₄ are each independently selected fromhydrogen or R_(A); W₁, W₂, W₃ and W₄ are N; Z₁ and Z₂ are independently—N(R_(B))— (e.g., —NH— or —N(C₁-C₆alkyl)—); and at least one of X₁ andX₂ is —CH₂—, —O—, or —S—. Preferably, at least one of R₇ and R₈ isphenyl, and is optionally substituted with one or more R_(A). Morepreferably, R₁ and R₂ are hydrogen; and R₉, R₁₀, R₁₁, R₁₂, R₁₃, and R₁₄are each independently selected from hydrogen; halogen; or C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆carbocyclyl, orC₃-C₆carbocyclylC₁-C₆alkyl, each of which is independently optionallysubstituted at each occurrence with one or more substituents selectedfrom halogen, hydroxy, mercapto, amino, carboxy, nitro, phosphate, oxo,thioxo, formyl or cyano. Highly preferably, R₉ and R₁₂ are eachindependently selected from C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₃-C₆carbocyclyl (e.g., C₃-C₆cycloalkyl), or C₃-C₆carbocyclyC₁-C₆alkyl(e.g., C₃-C₆cycloalkylC₃-C₆alkyl), each of which is independentlyoptionally substituted at each occurrence with one or more substituentsselected from halogen, hydroxy, mercapto, amino, carboxy, nitro,phosphate, oxo, thioxo, formyl or cyano; and R₁₀, R₁₁, R₁₃ and R₁₄ arehydrogen.

In yet another embodiment, R₃ and R₄, taken together with the carbonatoms to which they are attached, form

R₅ and R₆, taken together with the carbon atoms to which they areattached, form

R₉, R₁₀, R₁₁, R₁₂, R₁₃, and R₁₄ are each independently selected fromhydrogen or R_(A); W₁, W₂, W₃ and W₄ are N; Z₁ and Z₂ are independently—N(R_(B))— (e.g., —NH— or —N(C₁-C₆alkyl)—); and X₁ and X₂ are eachindependently selected from —CH₂—, —O—, or —S—. Preferably, R₄ and R₈are phenyl, and are each optionally substituted with one or more R_(A).More preferably, R₁ and R₂ are hydrogen; and R₉, R₁₀, R₁₁, R₁₂, R₁₃, andR₁₄ are each independently selected from hydrogen; halogen; C₃-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆carbocyclyl, orC₃-C₆carbocyclyC₁-C₆alkyl, each of which is independently optionallysubstituted at each occurrence with one or more substituents selectedfrom halogen, hydroxy, mercapto, amino, carboxy, nitro, phosphate, oxo,thioxo, formyl or cyano. Highly preferably, R₉ and R₁₂ are eachindependently C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆carbocyclyl(e.g., C₃-C₆cycloalkyl), or C₃-C₆carbocyclyC₁-C₆alkyl (e.g.,C₃-C₆cycloalkylC₁-C₆alkyl), each of which is independently optionallysubstituted at each occurrence with one or more substituents selectedfrom halogen, hydroxy, mercapto, amino, carboxy,nitro, phosphate, oxo,thioxo, formyl or cyano; and R₁₀, R₁₁, R₁₃ and R₁₄ are hydrogen.

In another embodiment, R₃ and R₄ are each independently selected fromhydrogen or R_(A), and/or R₅ and R₆ are each independently selected fromhydrogen or R_(A); and at least one of R₇ and R₈ is a 5- to 6-memberedcarbocycle or heterocycle (e.g., phenyl), which is optionallysubstituted with one or more R_(A). Preferably, R₇ and R₈ are eachindependently selected from 5- to 6-membered carbocycles orheterocycles, and are each independently optionally substituted with oneor more R_(A).

In still another embodiment, R₃ and R₄ are each independently selectedfrom hydrogen or R_(A), and/or R₅ and R₆ are each independently selectedfrom hydrogen or R_(A); A₁ is a 5- to 6-membered carbocycle orheterocycle (e.g., phenyl, thiazolyl, thienyl, pyrrolidinyl orpiperidinyl), which is substituted with —X₁—R₇ and is optionallysubstituted with one or more R_(A); and A₂ is a 5- to 6-memberedcarbocycle or heterocycle (e.g., phenyl, thiazolyl, thienyl,pyrrolidinyl or piperidinyl), which is substituted with —X₂—R₈ and isoptionally substituted with one or more R_(A). Both A₁ and A₂ preferablyare phenyl, and are substituted with —X₁—R₇ and —X₂—R₈, respectively. X₁and X₂ preferably are independently selected from —CH₂—, —O— or —S—. R₇and R₈ preferably are each independently selected from 5- to 6-memberedcarbocycles or heterocycles, and are each independently optionallysubstituted with one or more R_(A). More preferably, R₇ and R₈ arephenyl, and are each independently optionally substituted with one ormore R_(A). W₁, W₂, W₃ and W₄ preferably are N. Z₁ and Z₂ preferably areindependently —N(R_(B))—, such as —NH—, —N(C₁-C₆alkyl)—,—N(C₂-C₆alkenyl)—, —N(C₂-C₆alkynyl)—, —N(C₁-C₆haloalkyl)—,—N(C₂-C₆haloalkenyl)—, or —N(C₂-C₆haloalkynyl)—. More preferably, Z₁ andZ₂ are independently selected from —NH— or —N(C₁-C₆alkly)—.

The present invention also features compounds having Formula II, andpharmaceutically acceptable salts thereof,

wherein

-   -   X₁ and X₂ are each independently selected from a bond, —L_(S)—,        —O—, —S—, or —N(R_(B))—;    -   R₇ and R₈ are each independently selected from hydrogen, —L_(A),        C₅-C₁₀carbocyclyl, or 5- to 10-membered heterocyclyl, wherein at        each occurrence said C₅-C₁₀carbocyclyl and 5- to 10-membered        heterocyclyl are each independently optionally substituted with        one or more R_(A);    -   W₁, W₂, W₃, W₄, W₅, W₆, W₇, and W₈ are each independently        selected from N or C(R_(D)), wherein R_(D) is independently        selected at each occurrence from hydrogen or R_(A);    -   R₁, R₂, R₉, R₁₁, R₁₂, R₁₄, R₁₅, and R₁₆ are each independently        selected at each occurrence from hydrogen or R_(A);    -   m and n are independently selected from 0, 1, 2, or 3;    -   T is selected from a bond, —L_(S)—, —L_(S)—M—L_(S)—,        —L_(S)—M—L_(S)—M′—L_(S)—, wherein M and M′are each independently        selected from a bond, —O—, —S—, —N(R_(B))—, —C(O)—, —S(O)—,        —OS(O)—, —OS(O)₂—, —S(O)₂O—, —S(O)O—, —C(O)O—, —OC(O)—,        —OC(O)O—, —C(O)N(R_(B))—, —N(R_(B)(C(O)—, —N(R_(B))C(O)O—,        —OC(O)N(R_(B))—, —N(R_(B))S(O)—, —N(R_(B))S(O)₂, —S(O)N(R_(B))—,        —S(O)₂N(R_(B))—, —C(O)N(R_(B))C(O)—, —N(R_(B))C(O)N(R_(B′))—,        —N(R_(B))SO₂N(R_(B′))—, —N(R_(B))S(O)N(R_(B′))—,        C₅-C₁₀carbocycle, or 5- to 10-membered heterocycle, and wherein        R is optionally substituted with one or more R_(A);    -   R_(A) is independently selected at each occurrence from halogen        ,hydroxy, mercapto, amino, carboxy, nitro, phosphate, oxo,        thioxo, formyl, cyano, —L_(A), or —L_(S)—R_(B);    -   R_(B) and R_(B′) are each independently selected at each        occurrence from hydrogen; or C₁-C₆alkyl, C₂-C₆alkenyl,        C₂-C₆alkynyl, C₃-C₆carbocyclyl, C₃-C₆carbocyclylC₁-C₆alkyl, 3-        to 6-membered heterocyclyl, or (3- or 6-membered        heterocyclyl)C₁-C₆alkyl, each of which is independently        optionally substituted at each occurrence with one or more        substituents selected from halogen, hydroxy, mercapto, amino,        carboxy, nitro, phosphate, oxo, thioxo, formyl or cyano;    -   R_(C) and R_(C)′ are each independently selected at each        occurrence from hydrogen; halogen; hydroxy; mercapto; amino;        carboxy; nitro; phosphate; oxo; thioxo; formyl; cyano; or        C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, or C₃-C₆carbocyclyl,        each of which is independently optionally substituted at each        occurrence with one or more substituents selected from halogen,        hydroxy, mercapto, amino, carboxy, nitro, phosphate, oxo,        thioxo, formyl or cyano;    -   L_(A) is independently selected at each occurrence from        C₁-C₆alkyl, C₂-C₆alkenyl, or C₂-C₆alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —O—R_(S), —S—R_(S),        —N(R_(S)R_(S′)), —OC(O)R_(S), —C(O)OR_(S), nitro, phosphate,        oxo, thioxo, formyl or cyano;    -   L_(S), L_(S′) and L_(S″) are each independently selected at each        occurrence from a bond; or C₁-C₆alkylene, C₂-C₆alkenylene, or        C₂-C₆alkynylene, each of which is independently optionally        substituted at each occurrence with one or more substituents        selected from halogen, —O—R_(S), —S—R_(S), —N(R_(S)R_(S′)),        —OC(O)R_(S), —C(O)OR_(S), nitro, phosphate, oxo, thioxo, formyl        or cyano;    -   R_(E) is independently selected at each occurrence from        —O—R_(S), —S—R_(S), —C(O)R_(S), —OC(O)R_(S), —C(O)OR_(S),        —N(R_(S)R_(S′)), —S(O)R_(S), —SO₂R₈, —C(O)N(R_(S)R_(S′)),        —N(R₈)C(O)R_(S′), —N(R_(S))C(O)N(R_(S), R_(S″)),        —N(R_(S))SO₂R_(S′), —SO₂N(R_(S)R_(S′)),        —N(R_(S))SO₂N(R_(S′)R_(S″)), —N(R_(S))S(O)N(R_(S′)R_(S″)).        —OS(O)—R_(S), —OS(O)₂—R_(S), —S(O)₂OR_(S), —S(O)OR_(S),        —OC(O)OR_(S), —N(R_(S))C(O)OR_(S′), —OC(O)N(R_(S)R_(S′)),        —N(R_(S))S(O)—R_(S′), —S(O)N(R_(S)R_(S′)),        —C(O)N(R_(S))C(O)—R_(S′, C) ₃-C₆carbocyclyl, or 3- to 6-membered        heterocyclyl, and said C₃-C₆carbocyclyl and 3- to 6-membered        heterocyclyl are each independently optionally substituted at        each occurrence with one or more substituents selected from        C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, R_(S) (except hydrogen),        halogen, —O—R_(B), —S—R_(B), —N(R_(B)R_(B′)), —OC(O)R_(B),        —C(O)OR_(B), nitro, phosphate, oxo, thioxo, formyl or cyano; and    -   R_(S), R_(S′) and R_(S″) are each independently selected at each        occurrence from hydrogen; or C₁-C₆alkyl, C₂-C₆alkenyl,        C₂-C₆alkynyl, C₃-C₆carbocyclyl, C₃-C₆carbocyclylC₃-C₆alkyl, 3-        to 6-membered heterocyclyl, or (3- to 6-membered        heterocyclyl)C₃-C₆alkyl, each of which is independently        optionally substituted at each occurrence with one or more        substituents selected from halogen, —O—R_(B), —S—R_(B),        —N(R_(B)R_(B′)), —OC(O)R_(B), —C(O)OR_(B), nitro, phosphate,        oxo, thioxo, formyl or cyano.

Z₁ and Z₂ are preferably independently —N(R_(B))—, such as —NH— or—N(C₃-C₆alkyl)—.

X₁ and X₂ are preferably independently selected from —CH₂—, —O—, or —S.

R₇ and R₈ are preferably independently selected from C₅-C₆carbocycles or5- to 6-membered heterocycles, and are each independently optionallysubstituted with one or more R_(A). The ring system in R₇ can beidentical to, or different from, that in R₈. More preferably, both R₇and R₈ are phenyl, and are each independently optionally substitutedwith one or more R_(A) (e.g., —N(R_(S)R_(S′)) such as —NH₂).

T can be selected, without limitation, from the following moieties:

where k is 1 or 2, R and R* are independently hydrogen or C₁-C₆alkyl,and R′ and R″ are independently C₁-C₆alkyl or C₆-C₁₀aryl.

Preferably, T is selected from Table 4 described below.

More preferably, T is —L_(S)—N(R_(T))—L_(S)— (e.g., —CH₂—N(R_(T))—CH₂—),or —L_(S)—C(R_(T)R_(T)′)—L_(S)— (e.g., —CH₂—C(R_(T)R_(T)′)—CH₂—). R_(T)is C₁-C₆alkyl, C₂-C₆alkenyl, or C₂-C₆alkynyl, each of which isindependently optionally substituted at each occurrence with one or moresubstituents selected from halogen, —O—R_(S), —S—R_(S), —N(R_(S)R_(S′)),—OC(O)R₈, nitro, phosphate, oxo, thioxo, formyl or cyano; or R_(T) isC₃-C₆carbocyclyl, C₃-C₆carbocyclylC₁-C₆alkyl, 3- to 6-memberedheterocycle, or 3- or 6-membered heterocyclyl)C₁-C₆alkyl, each of whichis independently optionally substituted at each occurrence with one ormore substituents selected from C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,R_(S) (except hydrogen), halogen, —O—R_(B), —S—R_(B), —N(R_(B)R_(B′)),—OC(O)R_(B), —C(O)OR_(B), nitro, phosphate, oxo, thioxo, formyl orcyano, R_(T) is R_(A), and preferably R_(T) is hydrogen. L_(S), L_(S′),R_(A), R_(B), R_(B′), R_(S), and R_(S′) are as defined above.

In one embodiment, at least one of X₁ and X₂ is selected from —CH₂—,—O—, or —S—; at least one of R₇ and R₈ is selected from 5- to 6-memberedcarbocycles or heterocycles, and is optionally substituted with one ormore R_(A); and Z₁ and Z₂ are each independently —N(R_(B))— (e.g., —NH—or —N(C₁-C₆alkyl)—).

In another embodiment, X₁ and X₂ are each independently selected from—CH₂—, —O—, or —S—; R₇ and R₈ are each independently selected fromC₃-C₆carbocycles or 5- to 6-membered heterocycles, and are eachindependently optionally substituted with one or more R_(A); and Z₁ andZ₂ are each independently —N(R_(B))— (e.g., —NH— or —N(C₃-C₆alkyl)—).

In still another embodiment, W₁, W₂, W₃, W₄, W₅, and W₇ are N, and W₆and W₈ are each independently C(R_(D)); R₁ and R₂ are hydrogen; R₇ andR₈ are phenyl, and are each independently optionally substituted withone or more R_(A); and R₉, R₁₁, R₁₂, R₁₄, and R_(D) are eachindependently selected at each occurrence from hydrogen; halogen;C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆carbocyclyl, orC₃-C₆carbocyclylC₁-C₆alkyl, each of which is independently optionallysubstituted at each occurrence with one or more substituents selectedfrom halogen, hydroxy, mercapto, amino, carboxy, nitro, phosphate, oxo,thioxo, formyl or cyano. Preferably, R₉ and R₁₂ are each independentlyC₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆carbocyclyl (e.g.,C₃-C₆cycloalkyl), or C₃-C₆carbocyclyC₁-C₆alkyl (e.g.,C₃-C₆cycloalkylC₁-C₆alkyl), each of which is independently optionallysubstituted at each occurrence with one or more substituents selectedfrom halogen, hydroxyl, mercapto, amino, carboxy, nitro, phosphate, oxo,thioxo, formyl or cyano; and R₁₃, R₁₄ and R_(D) are hydrogen.

The present invention further features compounds having Formula III, andpharmaceutically acceptable salts thereof.

wherein:

-   -   X₁ and X₂ are each independently selected from a bond, —L_(S)—,        —O—, —S—, or —N(R_(B))—;    -   R₇ and R₈ are each independently selected from hydrogen,        —L_(A)—, C₅-C₁₀carbocyclyl, or 5- to 10-membered heterocyclyl,        wherein at each occurrence said C₅-C₁₀carbocyclyl and 5- to        10-membered heterocyclyl are each independently optionally        substituted with one or more R_(A);    -   Z₁ and Z₂ are each independently selected from a bond,        —C(R_(C)R_(C′))—, —O—, —S—, or —N(R_(B))—;    -   W₁, W₂, W₃, W₄, W₅, W₆, W₇, and W₈ are each independently        selected from N or C(R_(D)), wherein R_(D) is independently        selected at each occurrence from hydrogen or R_(A);    -   R₁, R₂, R₉, R₁₁, R₁₂, R₁₄, R₁₅, and R₁₆ are each independently        selected at each occurrence from hydrogen or R_(A);    -   m and n are each independently selected from 0, 1, 2, or 3;    -   T is selected from a bond, —L_(S)—, —L_(S)—M—L_(S)—,        —L_(S)–M—L₂—M′—L_(S)—, wherein M and M′ are each independently        selected from a bond, —O—, —S—, 13 N(R_(B))—, —C(O)—, —S(O)₂—,        —S(O)—, —OS(O)—, —OS(O)₂—, —S(O)₂O—, —S(O)O—, —C(O)O—, —OC(O)—,        —OC(O)O—, —C(O)N(R_(B))—, —N(R_(B))C(O)—, —N(R_(B))C(O)O—,        OC(O)N(R_(B))—, N(R_(B))S(O)—, —N(R_(B))S(O)₂—, —S(O)N(R_(B))—,        —S(O)₂N(R_(B))—, —C(O)N(R_(B))C(O)—, —N(R_(B))C(O)N(R_(B′))—,        —N(R_(B))SO₂N(R_(B′))—, —N(R_(B))S(O)N(R_(B′))—,        C₅-C₁₀carbocycle, or 5- to 10-membered heterocycle, and wherein        T is optionally substituted with one or more R_(A);    -   R_(A) is independently selected at each occurrence from halogen,        hydroxy, mercapto, amino, carboxy, nitro, phosphate, oxo,        thioxo, formyl, cyano, —L_(A), or —L_(S)—R_(B);    -   R_(B and R) _(B′) are each independently selected at each        occurrence from hydrogen; or C₁-C₆alkyl, C₂-C₆alkenyl,        C₂-C₆alkynyl, C₃-C₆carbocyclyl, C₃-C₆carbocyclylC₁-C₆alkyl, 3-        to 6-membered heterocyclyl, or (3- or 6-membered        heterocyclyl)C₁-C₆alkyl, each of which is independently        optionally substituted at each occurrence with one or more        substituents selected from halogen, hydroxy, mercapto, amino,        carboxy, nitro, phosphate, oxo, thioxo, formyl or cyano;    -   R_(C) and R_(C′) are each independently selected at each        occurrence from hydrogen; halogen; hydroxy; mercapto; amino;        carboxy; nitro; phosphate; oxo; thioxo; formyl; cyano; or        C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, or C₃-C₆carbocyclyl,        each of which is independently optionally substituted at each        occurrence with one or more substituents selected from halogen,        hydroxy, mercapto, amino, carboxy, nitro, phosphate, oxo,        thioxo, formyl or cyano;    -   L_(A) is independently selected at each occurrence from        C₁-C₆alkyl, C₂-C₆alkenyl, or C₂-C₆alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —O—R_(S), —S—R_(S),        —N(R_(S)R_(S′)), OC(O)R₈, —C(O)OR_(S), nitro, phosphate, oxo,        thioxo, formyl or cyano;    -   L_(S), L_(S′), and L_(S″) are each independently selected at        each occurrence from a bond; or C₁-C₆alkylene, C₂-C₆alkenylene,        or C₂-C₆alkynylene, each of which is independently optionally        substituted at each occurrence with one or more substituents        selected from halogen, —O—R_(S), —S—R_(S), —N(R_(S)R_(S)′),        —OC(O)R_(S), —C(O)OR₅, nitro, phosphate, oxo, thioxo, formyl or        cyano;    -   R_(E) is independently selected at each occurrence from        —O—R_(S), —S—R_(S), —C(O)R_(S), —OC(O)R_(S), —C(O)OR_(S),        —N(R_(S)R_(S′)), —N(R_(S))SO₂R_(S′), —SO₂N(R_(S)R_(S′)),        —N(R_(S))SO₂N(R_(S), R_(S″)), —N(R_(S))S(O)N(R_(S′)R_(S″)),        —OS(O)—R_(S), —OS(O)₂—R_(S), —S(O)₂OR_(S), —S(O)OR_(S),        —OC(O)OR_(S), —N(R_(S))C(O)OR_(S′), —OC(O)N(R_(S)R_(S′)),        —N(R_(S))S(O)—R_(S″), —S(O)N(R_(S)R_(S′)),        —C(O)N(R_(S))C(O)—R_(S′), C₃-C₆carbocyclyl, or 3- to 6-membered        heterocyclyl, and said C₃-Ccarbocyclyl and 3- to 6-membered        heterocyclyl are each independently optionally substituted at        each occurrence with one or more substituents selected from        C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, R_(S) (except hydrogen),        halogen, 13 O—R_(B), —S—R_(B), —N(R_(B)R_(B′)), —OC(O)R_(B),        —C(O)OR_(B), nitro, phosphate, oxo, thioxo, formyl or cyano; and    -   R_(S), R_(S′) and R_(S″) are each independently selected at each        occurrence from hydrogen; or C₁-C₆alkyl, C₂-C₆alkenyl,        C₂-C₆alkynyl, C₃-C₆carbocyclyl, C₃-C₆carbocyclylC₁-C₆alkyl, 3-        to 6-membered heterocyclyl or (3- to 6-membered        heterocyclyl)C₁-C₆alkyl, each of which is independently        optionally substituted at each occurrence with one or more        substituents selected from halogen, —O—R_(B), —S—R_(B),        —N(R_(B)R_(B′)), —OC(O)R_(B), —C(O)OR_(B), nitro, phosphate,        oxo, thioxo, formyl or cyano.    -   Z₁ and Z₂ are preferably each independently —N(R_(B))—, such as        —NH— or —N(C₁-C₆alkyl)—.    -   X₁ and X₂ are preferably independently selected from —CH₂—, —O—,        or —S.    -   R₇ and R₈ are preferably independently selected from        C₅-C₆carbocycles or 5- to 6-membered heterocycles, and are each        independently optionally substituted with one or more R_(A). The        ring system in R₇ can be identical to, or different from, that        in R₈. More preferably, both R₇ and R₈ are phenyl, and are each        independently optionally substituted with one or more R_(A)        (e.g., —N(R_(S)R_(S′)) such as —NH₂).

T can be selected, without limitation, from the following moieties:

where k is 1 or 2, R and R* are independently hydrogen or C₁-C₆alkyl,and R′ and R″ are independently C₁-C₆alkyl or C₆-C₁₀aryl.

Preferably, T is selected from Table 4 described below.

More preferably, T is —L_(S)—N(R_(T))—L_(S)—(e.g., —CH₂—N(R_(T))—CH₂—),or —L_(S)—C(R_(T)R_(T′))—L_(S)— (e.g., —CH₂—C(R_(T)R_(T′))—CH₂—). R_(T)is C₁-C₆alkyl, C₂-C₆alkenyl, or C₂-C₆alkynyl, each of which isindependently optionally substituted at each occurrence with one or moresubstituents selected from halogen, —O—R_(S), —S—R_(S), —N(R_(S)R_(S′)),—OC(O)R_(S), —C(O)OR_(S), nitro, phosphate, oxo, thioxo, formyl orcyano; or R_(T) is C₃-C₆carbocyclyl, C₃-C₆carbocyclylC₁-C₆alkyl, 3- to6-membered heterocyclyl, or (3- or 6-membered heterocyclyl)C₁-C₆alkyl,each of which is independently optionally substituted at each occurrencewith one or more substituents selected from C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, R_(S) (except hydrogen), halogen, —O—R_(B), —S—R_(B),—N(R_(B)R_(B′)), —OC(O)R_(B), —C(O)OR_(B), nitro, phosphate, oxo,thioxo, formyl or cyano. R_(T′) is R_(A), and preferably R_(T′) ishydrogen. L_(S), L_(S′), R_(A), R_(B), R_(B′), R_(S), and R_(S′) are asdefined above.

In one embodiment, at least one of X₁ and X₂ is selected from —CH₂—,—O—, or —S—; at least one of R₇ and R₈ is selected from 5- to 6-memberedcarbocycles or heterocycles, and is optionally substituted with one ormore R_(A); and Z₁ and Z₂ are each independently —N(R_(B))— (e.g., —NH—or —N(C₁-C₆alkyl)—).

In another embodiment, X₁ and X₂ are each independently selected from—CH₂—, —O—, or —S—; R₇ and R₈ are each independently selected fromC₅-C₆carbocycles or 5- to 6-membered heterocycles, and are eachindependently optionally substituted with one or more R_(A); and Z₁ andZ₂ are each independently —N(R_(B))— (e.g., —NH— or —N(C₁-C₆alkyl)—).

In still another embodiment, W₁, W₂, W₃, W₄, W₅, and W₇ are N, and W₆and W₈ are each independently C(R_(D)); R₁ and R₂ are hydrogen; R₇ andR₈ are phenyl, and are each independently optionally substituted withone or more R_(A); and R₉, R₁₁, R₁₂, R₁₄, and R_(D) are eachindependently selected at each occurrence from hydrogen; halogen; orC₃-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆carbocyclylalkyl, orC₃-C₆carbocyclylC₁-C₆carbocyclylC₁-C₆alkyl, each of which isindependently optionally substituted at each occurrence with one or moresubstituents selected from halogen, hydroxy, mercapto, amino, carboxy,nitro, phosphate, oxo, thioxo, formyl or cyano. Preferably, R₉ and R₁₂are each independently C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₃-C₆carbocyclyl (e.g., C₃-C₆cycloalkyl), or C₃-C₆carbocyclyC₁-C₆alkyl(e.g., C₃-C₆cycloalkylC₁-C₆alkyl), each of which is independentlyoptionally substituted at each occurrence with one or more substituentsselected from halogen, hydroxy, mercapto, amino, carboxy, nitro,phosphate, oxo, thioxo, formyl or cyano; and R₁₁, R₁₄ and R_(D) arehydrogen.

The compounds of the present invention can be used in the form of salts.Depending on the particular compound, a salt of a compound may beadvantageous due to one or more of the salt's physical properties, suchas enhanced pharmaceutical stability under certain conditions or desiredsolubility in water or oil. In some instances, a salt of a compound maybe useful for the isolation or purification of the compound.

Where a salt is intended to be administered to a patient, the saltpreferably is pharmaceutically acceptable. Pharmaceutically acceptablesalts include, but are not limited to, acid addition salts, baseaddition salts, and alkali metal salts.

Pharmaceutically acceptable acid addition salts may be prepared frominorganic or organic acids. Examples of suitable inorganic acidsinclude, but are not limited to, hydrochloric, hydrobromic acid,hydroionic, nitric, carbonic, sulfuric, and phosphoric acid. Examples ofsuitable organic acids include, but are not limited to, aliphatic,cycloaliphatic, aromatic, aliphatic, heterocyclyl, carboxylic, andsulfonic classes of organic acids. Specific examples of suitable organicacids include acetate, trifluoroacetate, formate, propionate, succinate,glycolate, gluconate, digluconate, lactate, malate, tartaric acid,citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate,glutamate, benzoate, anthranilic acid, mesylate, stearate, salicylate,p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate),methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate,toluenesulfonate, 2-hydroxyethanesulfonate, sufanilate,cyclohexylaminosulfonate, algenic acid, b-hydroxybutyne acid,galactarate, galacturonate, adipate, alginate, bisultate, butyrate,camphorate, camphorsulfonate, cyclopentanepropionate, dodecylsulfate,glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate,nicotinate, 2-naphthalesulfonate, oxalate, palmoate, pectinate,persulfate, 3-phenylpropionate, picrate, pivalate, thiocyanate,tosylate, and undecanoate.

Pharmaceutically acceptable base addition salts include, but are notlimited to, metallic salts and organic salts. Non-limiting examples ofsuitable metallic salts include alkali metal (group Ia) salts, alkalineearth metal (group IIa) salts, and other pharmaceutically acceptablemetal salts. Such salts may be made, without limitation, from aluminum,calcium, lithium, magnesium, potassium, sodium, or zinc. Non-limitingexamples of suitable organic salts can be made from tertiary amines andquaternary amine, such as tromethamine, diethylamine,N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine), and procaine. Basicnitrogen-containing groups can be quaternized with agents such as alkylhalides (e.g., methyl, ethyl, propyl, butyl, decyl, lauryl, myristyl,and stearyl chlorides/bromides/iodides), dialkyl sulfates (e.g.,dimethyl, diethyl, dibutyl, and diamyl sulfates), aralkyl halides (e.g.,benzyl and phenethyl bromides), and others.

The compound or salts of the present invention may exist in the form ofsolvates, such as with water (i.e., hydrates), or with organic solvents(e.g., with methanol, ethanol or acetonitrile to form, respectively,methanolate, ethanolate or acetonitrilate).

The compounds or salts of the present invention may also be used in theform of prodrugs. Some prodrugs are aliphatic or aromatic esters derivedfrom acidic groups on the compounds of the invention. Others arealiphatic or aromatic esters of hydroxyl or amino groups on thecompounds of the invention. Phosphate prodrugs of hydroxyl groups arepreferred prodrugs.

The compounds of the invention may comprise asymmetrically substitutedcarbon atoms known as chiral centers. These compounds may exist, withoutlimitation, as single stereoisomers (e.g., single enantiomers or singlediastereomer), mixtures of stereoisomers (e.g. a mixture of enantiomersor diastereomers), or racemic mixtures. Compounds identified herein assingle stereoisomers are meant to describe compounds that are present ina form that is substantially free from other stereoisomers (e.g.,substantially free from other enantiomers or diastereomers). By“substantially free,” it means that at least 80% of the compound in acomposition is the described stereoisomer; preferably, at least 90% ofthe compound in a composition is the described stereoisomer; and morepreferably, at least 95%, 96%, 97%, 98% or 99% of the compound in acomposition is the described stereoisomer. Where the stereochemistry ofa chiral carbon is not specified in the chemical structure of acompound, the chemical structure is intended to encompass compoundscontaining either stereoisomer of the central center.

Individual stereoisomers of the compounds of this invention can beprepared using a variety of methods known in the art. These methodsinclude, but are not limited to, stereospecific synthesis,chromatographic separation of diastereomers, chromatographic resolutionof enantiomers, conversion of enantiomers in an enantiomeric mixture todiastereomers followed by chromatographically separation of thediastereomers and regeneration of the individual enantiomers, andenzymatic resolution.

Stereospecific synthesis typically involves the use of appropriateoptically pure (enantiomerically pure) or substantial optically purematerials and synthetic reactions that do not cause racemization orinversion of stereochemistry at the chiral centers. Mixtures ofstereoisomers of compounds, including racemic mixtures, resulting from asynthetic reaction may be separated, for example, by chromatographictechniques as appreciated by those of ordinary skill in the art.Chromatographic resolution of enantiomers can be accomplished by usingchiral chromatography resins, many of which are commercially available.In a non-limiting example, racemate is placed in solution and loadedonto the column containing a chiral stationary phase. Enantiomers canthen be separated by HPLC.

Resolution of enantiomers can also be accomplished by convertingenantiomers in a mixture to diastereomers by reaction with chiralauxiliaries. The resulting diastereomers can be separated by columnchromatography or crystallization/re-crystallization. This technique isuseful when the compounds to be separated contain a carboxyl, amino orhydroxyl group that will form a salt or covalent bond with the chiralauxiliary. Non-limiting examples of suitable chiral auxiliaries includechirally pure amino acids, organic carboxylic acids or organosulfonicacids. Once the diastereomers are separated by chromatography, theindividual enantiomers can be regenerated. Frequently, the chiralauxiliary can be recovered and used again,

Enzymes, such as esterases, phosphatases or lipases, can be useful forthe resolution of derivatives of enantiomers in an enantiomeric mixture.For example, an ester derivative of a carboxyl group in the compounds tobe separated can be treated with an enzyme which selectively hydrolyzesonly one of the enantiomers in the mixture. The resultingenantiomerically pure acid can then be separated from the unhydrolyxedester.

Alternatively, salts of enantiomers in a mixture can be prepared usingany method known in the art, including treatment of the carboxylic acidwith a suitable optically pure base such as alkaloids or phenethylamine,followed by precipitation or crystallization/re-crystallization of theenantiotomerically pure salts. Methods suitable for theresolution/separation of a mixture of stereoisomers, including racemicmixtures, can be found in ENANTIOMERS, RACEMATES, AND RESOLUTIONS(Jacques et al., 1981, John Wiley and Sons, New York, N.Y.).

A compound of this invention may possess or more unsaturatedcarbon-carbon double bonds. All double bond isomers, such as the cis (Z)and trans (E) isomers, and mixtures thereof are intended to beencompassed within the scope of a recited compound unless otherwisespecified. In addition, where a compound exists in various tautomericforms, a recited compound is not limited to any one specific tautomer,but rather is intended to encompass all tautomeric forms.

Certain compounds of the invention may exist in different stableconformational forms which may be separable. Torsional asymmetry due torestricted rotations about an asymmetric single bond, for examplebecause of steric hindrance or ring strain, may permit separation ofdifferent conformers. The compounds of the invention includes each,conformational isomer of these compounds and mixtures thereof.

Certain compounds of the invention may also exist in zwitterionic formand the invention includes each zwitterionic form of these compounds andmixtures thereof.

The compounds of the present invention are generally described hereinusing standard nomenclature. For a recited compound having asymmetriccenter(s), it should be understood that all of the stereoisomers of thecompound and mixtures thereof are encompassed in the present inventionunless otherwise specified. Non-limiting examples of stereoisomersinclude enantiomers, diastereomers, and cis-transisomers. Where arecited compound exists in various tautomeric forms, the compound isintended to encompass all tautomeric forms. Certain compounds aredescribed herein using general formula that include variables (e.g., A₁,A₂, Z₁, Z₂, R₁ or R₂). Unless otherwise specified, each variable withinsuch a formula is defined independently at each occurrence. If moietiesare described as being “independently” selected from a group, eachmoiety is selected independently from the other. Each moiety thereforecan be identical to or different from the other moiety or moieties.

The number of carbon atoms in a hydrocarbyl moiety can be indicated bythe prefix “C_(x)-C_(y)” where x is the minimum and y is the maximumnumber of carbon atoms in the moiety. Thus, for example, “C₁-C₆alkyl”refers to an alkyl substituent containing from 1 to 6 carbon atoms.Illustrating further, C₃-C₆alkyl means a saturated hydrocarbyl ringcontaining from 3 to 6 carbon ring atoms. A prefix attached to amultiple-component substituent only applies to the first component thatimmediately follows the prefix. To illustrate, the term“carbocyclylalkyl” contains two components: carbocyclyl and alkyl. Thus,for example, C₃-C₆carbocyclylC₁-C₆alkyl refers to a C₃-C₆carbocyclylappended to the parent molecular moiety through a C₁-C₆alkyl group.

When words are used to describe a linking element between, two otherelements of a depicted chemical structure, the leftmost-describedcomponent of the linking element is the component that is bound to theleft element in the depicted structure. To illustrate, if the chemicalstructure is A₁—T—A₂ and T is described as —N(R_(B))S(O)13 , then thechemical will be A₁—N(R_(B))—S(O)—A₂.

If a linking element in a depicted structure is a bond, then the leftelement in the depicted structure is joined directly to the rightelement in the depicted structure. For example, if a chemical structureis depicted as —L_(S)—M—L_(S)—, where M is selected as a bond, then thechemical structure will be —L_(S)—L_(S)—. For another example, if achemical moiety is depicted as —L_(S)—R_(E) where L_(S) is selected as abond, then the chemical moiety will be —R_(E).

When a chemical formula is used to describe a moiety, the dash(s)indicates the portion of the moiety that has the free valence(s).

If a moiety is described as being “optionally substituted”, the moietymay be either substituted or unsubstituted. If a moiety is described asbeing optionally substituted with up to a particular number ofnon-hydrogen radicals, that moiety may be either unsubstituted, orsubstituted by up to that particular number of non-hydrogen radicals orby up to the maximum number of substitutable positions on the moiety,whichever is less. Thus, for example, if a moiety is described as aheterocycle optionally substituted with up to three non-hydrogenradicals, then any heterocycle with less than three substitutablepositions will be optionally substituted by up to only as manynon-hydrogen radicals as the heterocycle has substitutable positions. Toillustrate, tetrazolyl (which has only one substitutable position) willbe optionally substituted with up to one nonhydrogen radical. Toillustrate further, if an amino nitrogen is described as beingoptionally substituted with up to two non-hydrogen radicals, then aprimary amino nitrogen will be optionally substituted with up to twonon-hydrogen radicals, whereas a secondary amino nitrogen will beoptionally substituted with up to only one non-hydrogen radical.

The term “alkenyl” means a straight or branched hydrocarbyl chaincontaining one or more double bonds. Each carbon-carbon double bond mayhave either cis or turns geometry within the aklenyl moiety, relative togroups substituted on the double bond carbons. Non-limiting examples ofalkenyl groups include ethenyl (vinyl), 2-propenyl, 3-propenyl,1,4-pentadienyl, 1,4-butadienyl, 1-butenyl, 2-butenyl, and 3-butenyl.

The term “alkenylene” refers to a divalent unsaturated hydrocarbyl chainwhich may be linear or branched and which has at least one carbon-carbondouble bond. Non-limiting examples of alkenylene groups include—C(H)═C(H)—, —C(H)═C(H)—CH₂—, —C(H)═C(H)—CH₂—CH₂—, —CH—C(H)═C(H)—CH₂—,—C(H)═C(H)—CH(CH₃)—, and —CH₂—C(H)═CH(CH₂CH₃)—.

The term “alkyl” means a straight or branched saturated hydrocarbylchain. Non-limiting examples of alkyl groups include methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl,iso-amyl, and hexyl.

The term “alkylene” denotes a divalent saturated hydrocarbyl chain whichmay be linear or branched. Representative examples of alkylene include,but are not limited to, —CH₂—, —CH₂CH_(2—, —CH) ₂CH₂CH₂—,—CH₂CH₂CH₂CH₂—, and —CH₂CH(CH₃)CH₂—.

The term “alkynyl” means a straight or branched hydrocarbyl chaincontaining one or more triple bonds. Non-limiting examples of alkynylinclude ethynyl, 1-propynyl, 2-propynyl, 3-propynyl, decynyl, 1-butynyl,2-butynyl, and 3-butynyl.

The term “alkynylene” refers to a divalent unsaturated hydrocarbon groupwhich may be linear or branched and which has at least one carbon-carbontriple bonds. Representative alkynylene groups include, by way ofexample, —C≡C—, —C≡C—CH₂—, —C≡C—CH₂—CH₂—, —CH₂—C≡C—CH₂—, —C≡C—CH(CH₃)—,and —CH₂—C≡C—CH(CH₂CH₃)—.

The term “carbocycle” or “carbocyclic” or “carbocyclyl” refers to asaturated (e.g., “cycloalkyl”), partially saturated (e.g.,“cycloalkenyl” or “cycloalkynyl”) or completely unsaturated (e.g.,“aryl”) ring system containing zero heteroatom ring atom. “Ring atoms”or “ring members” are the atoms bound together to form the ring orrings. A carbocyclyl may be, without limitation, a single ring, twofused rings, or bridged or spiro rings. A substituted carbocyclyl mayhave either cis or trans geometry. Representative examples ofcarbocyclyl groups include, but are not limited to, cyclopropyl,cyclobutyl, cycopentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclopentenyl, cyclopentadienyl, cyclohexadienyl, adamantyl,decahydro-naphthalenyl, octahydro-indenyl, cyclohexenyl, phenyl,naphthyl, indanyl, 1,2,3,4k-tetrahydro-naphthyl, indenyl, isoindenyl,decalinyl, and norpinanyl. A carbocyclyl group can be attached to theparent molecular moiety through any substitutable carbon ring atom.Where a carbocyclyl group is a divalent moiety, such as A₁ and A₂ inFormula I, it can be attached to the remaining molecular moiety throughany two substitutable ring atoms.

The term “carbocyclylalkyl” refers to a carbocyclyl group appended tothe parent molecular moiety through an ethylene group. For instance,C₃-C₆carbocyclylC₁-C₆alkyl refers to a C₃-C₆carbocyclyl group appendedto the parent molecular moiety through C₁-C₆alkylene.

The term “cycloalkenyl” refers to a non-aromatic, partially unsaturatedcarbocyclyl moiety having zero heteroatom ring member. Representativeexamples of cycloalkenyl groups include, but are not limited to,cyclobutenyl, cyclopentenyl, cyclohexenyl, and oxtahydronaphthalenyl.

The term “cycloalkyl” refers to a saturated carbocyclyl group containingzero heteroatom ring member. Non-limiting examples of cycloalkylsinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, decalinyl and norpinanyl.

The prefix “halo” indicates that the substituent to which the prefix isattached is substituted with one or more independently selected halogenradicals. For example, “C₁-C₆haloalkyl” means a C₁-C₆alkyl substituentwherein one or more hydrogen atoms are replaced with independentlyselected halogen radicals. Non-limiting examples of C₁-C₆haloalkylinclude chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl,trifluomethyl, and 1,1,1-trifluoroethyl. It should be recognized that ifa substituent is substituted by more than one halogen radical, thosehalogen radicals may be identical or different (unless otherwisestated).

The term “heterocycle” or “heterocyclo” or “heterocyclyl” refers to asaturated (e.g., “heterocycloalkyl”), partially unsaturated (e.g.,“heterocycloalkenyl” or “heterocycloalkynyl”) or completely unsaturated(e.g., “heteroaryl”) ring system where at least one of the ring atoms isa heteroatom (i.e., nitrogen, oxygen or sulfur), with the remaining ringatoms being independently selected from the group consisting of carbon,nitrogen, oxygen, and sulfur. A heterocyclyl group can be linked to theparent molecular moiety via any substitutable carbon or nitrogen atom(s)in the group. Where a heterocyclyl group is a divalent moiety, such asA₁ and A₂ in Formula I, it can be attached to the remaining molecularmoiety through any two substitutable ring atoms.

A heterocyclyl may be, without limitation, a monocycle which contains asingle ring. Non-limiting examples of monocycles include furanyl,dihydrofuranyl, tetrahydrofuranyl, pyrrolyl, isopyrrolyl, pyrrolinyl,pyrrolidinyl, imidazolyl, isoimidazolyl, imidazolinyl, imidazolidinyl,pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, dithiolyl,oxathiolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl,isothiazolinyl, thiazolidinyl, isothiazolidinyl, thiodiazolyl,oxathiazolyl, oxadiazolyl (including 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl (also known as “azoximyl”), 1,2,5-oxadiazolyl (alsoknown as “furazanyl”), and 1,3,4-oxadiazolyl), oxatriazolyl (including1,2,3,4-oxatriazolyl and 1,2,3,5-oxatriazolyl), dioxazolyl (including1,2,3-dioxazolyl, 1,2,4-dioxazolyl, 1,3,2-dioxazolyl, and1,3,4-dioxazolyl), oxathiolanyl, pyranyl (including 1 ,2-pyranyl and1,4-pyranyl), dihydropyranyl, pyridinyl, piperidinyl, diazinyl(including pyridazinyl (also known as “1,2-diazinyl”), pyrimidinyl (alsoknown as “1,3-diazinyl”), and pyrazinyl (also known as “1,4-diazinyl”)),piperazinyl, triazinyl (including s-triazinyl (also known as“1,3,5-triazinyl”), as-triazinyl (also known 1,2,4-triazinyl), andv-triazinyl (also known as “1,2,3-triazinyl), oxazinyl (including1,2,3-oxazinyl, 1,3,2-oxazinyl, 1,3,6- oxazinyl (also known as“pentoxazolyl”), 1,2,6-oxazinyl, and 1,4-oxazinyl), isoxazinyl(including o-isoxazinyl and p-isoxazinyl), oxazolidimyl, isoxazolidinyl,oxathiazinyl (including 1,2,5-oxathiazinyl or 1,2,6-oxathiazinyl),oxadiazinyl (including 1,4,2-oxadiazinyl and 1,3,5,2-oxadiazinyl),morpholinyl, azepinyl, oxepinyl, thiepinyl, and diazepinyl.

A heterocyclyl may also be, without limitation, a bicycle containing twofused rings, such as, for example, naphthyridinyl (including [1,8]naphthyridinyl, and [1,6] naphthyridinyl), thiazolpyrimidinyl,thienopyrimidinyl, pyrimidopyrimidinyl, pyridopyrimidinyl,pyrazolopyrimidinyl, indolizinyl, pyrindinyl, pyranopyrrolyl,4H-quinolizinyl, pyrinyl, pyridopyridinyl (includingpyrido[3,4-b]-pyridinyl, pyrido[3,2-b]-pyridinyl, andpyrido[4,3-b]-pyridinyl), pyridopyrimidine, and pteridinyl. Othernon-limiting examples of fused-ring heterocycles include benzo-fusedheterocyclyis, such as incolyl, isoindolyl, indoleninyl (also known as“pseudoindolyl”), isoindazolyl (also known as “benzpyrazolyl”),benzazinyl (including quinolinyl (also known as “1-benzazinyl”) andisoquinolinyl (also known as “2-benzazinyl”)), phthalazinyl,quinoxalinyl, benzodiazinyl (including cinnolinyl (also known as“1,2-benzodiazinyl”) and quinazolinyl (also known as“1,3-benzodiazinyl”)), benzopyranyl (incuding “chromenyl” and“isochromenyl”), benzothiopyranyl (also known as “thiochromenyl”),benzoxazolyl, indoxazinyl (also known as “benzisoxazolyl”), anthranilyl,benzodioxoyly, benzodioxanyl, benzoxadiazolyl, benzofuranyl (also knownas “coumaronyl”), isobenzofuranyl, ebnzothienyl (also known as“benzothiophenyl”, “thionaphthenyl”, and “benzothiofuranyl”),benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl,benzosazinyl (including 1,3,2-benzoxazinyl, 1,4,2-benzoxazinyl2,3,1-benzoxazinyl, and 3,1,4-benzoxazinyl), benzisoxazinyl),benzisoxazinyl (including 1,2-benzisoxazinyl and 1,4-benzisoxazinyl),and tetrahydroisoquinolinyl.

A heterocyclyl may comprise one or more sulfur atoms as ring members;and in some cases the sulfur atom(s) is oxidized to SO or SO₂. Thenitrogen heteroatom(s) in a heterocyclyl may or may not be quaternized,and may or may not be oxidized to N-oxide. In addition, the nitrogenheteroatom(s) may or may not be N-protected.

The term “pharmaceutically acceptable” is used adjectivally to mean thatthe modified noun is appropriate for use as a pharmceutical product oras a part of a pharmaceutical product.

The term, “therapeutically effective amount” refers to the total amountof each active substance that is sufficient to show a meaningful patientbenefit, e.g. a reduction is viral load.

The term “prodrug” refers to derivatives of the compounds of theinvention which have chemically or metabolically cleavable groups andbecome, by solvolysis or under physiological conditions, the compoundsof the invention which are pharmaceutically active in vivo. A prodrug ofa compound may be formed in a conventional manner by reaction of afunctional group of the compound (such as an amino, hydroxy or carboxygroup). Prodrugs often offer advantages of solubility, tissuecompatibility, or delayed release in mammals (see, Bungard, H., DESIGNOF PRODRUGS, pp, 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs includeacid derivatives well known to practitioners of the art, such as, forexample, esters prepared by reaction of the parent acidic compound witha suitable alcohol, or amides prepared by reaction of the parent acidcompound with a suitable amine. Examples of prodrugs include, but arenot limited to, acetate, formate, benzoate or other acylated derivativesof alcohol or amine functional groups within the compounds of theinvention.

The term “solvate” refers to the physical association of a compound ofthis invention with one or more solvent molecules, whether organic orinorganic. This physical association often includes hydrogen bonding. Incertain instances the solvate will be capable of isolation, for examplewhen one or more solvent molecules are incorporated in the crystallattice of the crystalline solid. “Solvate” encompasses bothsolution-phase and isolable solvates. Exemplary solvates include, butare not limited to, hydrates, ethanolates, and methanolates.

The term “N-protecting group” or “N-protected” refers to those groupscapable of protecting an amino group against undesirable reactions.Commonly used N-protecting groups are described in Greene and Wuts,PROTECTING GROUPS IN cHEMICAL SYNTHESIS (3^(rd) ed., John Wiley & Sons,NY (1999). Non-limiting examples of N-protecting groups include acylgroups such as formyl, acetyl, propionyl, pivaloyl t-butylacetyl,2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl,phthalyl, o-nitrophenoxyacetyl, benzoyl, 4-chlorobenzoyl,4-bromobenzoyl, or 4-nitrobenzoyl; sulfonyl groups such asbenzenesulfonyl or p-toluenesulfonyl; sulfenyl groups such asphenylsulfenyl (phenyl-S-) or triphenylmethylsulfenyl (trityl-S-);sulfinyl groups such as p-methylphenylsulfinyl (p-methylphenyl-S(O)—) ort-butylsulfinyl (t-Bu-S(O)-); carbamate forming groups such asbenzyloxycarbonyl, p-chlorobenzyloxycarbonyl,p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl,3,4-dimethoxybenxyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl,2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,2-nitro-4,5-dimethoxybenzyloxycarbonyl,3,4,5-trimethoxybenzyloxycarbonyl,1(p-biphenylyl)-1-methylethyoxycarbonyl,dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl,t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl,ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl,2,2,2-trichloro-ethoxy-carbonyl, phenoxycarbonyl,4-nitro-phenoxycarbonyl, cyclopentyloxycarbonyl, adamanthloxycarbonyl,cyclohexyloxycarbonyl, or phenylthiocarbonyl; alkyl groups such asbenzyl, p-methoxybenzyl, triphenylmethyl, or benzyloxymethyl;p-methoxyphenyl; and silyl groups such as trimethylsilyl. PreferredN-protecting groups include formyl, acetyl, benzoly, pivaolyl,t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) andbenzyloxycarbonyl (Cbz).

The compounds of the present invention can be prepared by coupling acompound of Formula IV to a compound of Formula V as showed in Scheme 1,where A₁, A₂, Z₁, Z₂, W₁, W₂, W₃, W₄, R₁, R₂, R₃, R₄, R₅, R₆ and T aredefined hereinabove. Compounds of Forumulae IV and V can be preparedaccording to the processes described in U.S. Patent ApplicationPublication Nos. 20070232627, 20070197558 and 20070232645, andWO2008/133753.

As a non-limiting example, the compounds of the present invention can beprepared by coupling a compound of Formula IV to a compound of Formula Vas shown in Scheme II, where T₁ is a carboxylic acid as shown or anactivated derivative such as an acid chloride or an activated ester(e.g., N-hydroxysuccinimide or pentafluorophenyl esters), and T₂ is anamine or substituted amine. Amide bond coupling reagents such as DCC,EDAC, PyBOP, and HATU may be employed with the option of adding an aminebase such as triethylamine or Hunig's base in a solvent such as DMF,DMSO, THF, or dichloromethane.

As another non-limiting example, the compounds of the present inventioncan be prepared by coupling a compound of Formula IV to a compound ofFormula V as shown in Scheme III, where T₁ and T₂ are carboxylic acidsor activated derivatives such as acid chlorides or activated esters(e.g., N-hydroxysuccinimide or pentafluorophenyl esters) by reactionwith an amine or substituted amine as shown. Amide bond couplingreagents such as DCC, EDAC, PyBOP, and HATU may be employed with theoption of adding an amine base such as triethylamine or Hunig's base ina solvent such as DMF, DMSO, THF, or dichloromethane. Coupling may beconducted concurrently to give symmetric products or sequentially togive non-symmetric products. R_(B) and R_(B′) are as definedhereinabove, and —C(O)N(R_(B))—T′—N(R_(B′))C(O)— is T.

As yet another non-limiting example, the compounds of the presentinvention can be prepared by coupling a compound of Formula IV to acompound of Formula V as shown in Scheme IV, where T₁ and T₂ areindependently boronic acids or esters as shown by reaction withheterocyclic or carbocyclic halides (iodide shown in Scheme IV) ortriflates and a transition metal catalyst. T′ is a heterocyclic orcarbocyclic, and R can be, without limitation, independently selected ateach occurrence from hydrogen or L_(A), and L_(A) is as definedhereinabove. Alternatively, alkyl stannanes (such a tributyl- ortrimethylstannanes) may be employed in place of the boronates andcoupled with halides or triflates under analogous conditions. Pdcatalysts such as Pd(PPh₃)₄ or Pd(dppf)Cl₂ may be employed or generatedin situ using a Pd (II) catalyst such Pd(OAc)₂ or Pd₂(dba)₃ andorganophosphorous ligands, such as PPh₃ or P(t-Bu)₃. Reactions may beconducted with addition of a base such K₂CO₃ or K₃PO₄ in a solvent suchas THF or DMF. Couplings may be conducted concurrently to give symmetricproducts or sequentially to give non-symmetric products.

As still another non-limiting example, the compounds of the presentinvention can be prepared by coupling a compound of Formula IV to acompound of Formula V as shown in Scheme V, where T₁ and T₂ are halides(iodide as shown) by reaction with an alkyne, where R may betrimethylsilyl (TMS) or another suitable protecting group, bySonogashira reaction using a suitable catalyst. Pd catalysts such asPd(PPh₃)₄ or Pd(dppf)Cl₂ may be employed or generated in situ using a Pd(II) catalyst such Pd(OAc)₂ or Pd₂(dba)₃ and organophosphorous ligands,such as PPh₃ or P(t-Bu)₃. Alternatively, a Cu (I) catalyst may beemployed, such as Cu (I) iodide. Reactions may be conducted withaddition of a base such K₂CO₃ or K₃PO₄ or an amine base such astriethylamine or Hunig's base in a solvent such as THF or DMF. The TMSprotecting group may be removed using a base such as K₂CO₃ in a solventsuch as methanol or THF. A second Sonogashira reaction with V may beconducted under the analogous conditions to the first coupling.Couplings may be conducted concurrently to give symmetric products orsequentially to give non-symmetric products.

As a further non-limiting example, the compounds of the presentinvention can be prepared by coupling a compound of formula IV to acompound of Formula V as shown in Scheme VI. Formula IV and V are bothaldehydes, and can be reacted with an amine to form Formula VI (step 1)by reductive amination using a suitable reducing agent such as NaCNBH₃or NaBH(OAc)₃, in a solvent such as THF or ethanol with or without theaddition of acetic acid. R may be, without limitation, C₁-C₆alkyl suchas tert-butyl or isopropyl, C₆-C₁₀carbocycle such as phenyl, or 6- to10-membered heterocycle. Alternatively, R may be a protecting group,such as benzyl or 2,4-dimethoxy benzyl, which may be removed from VIusing hydrogenolysis or by treatment with an acid, such as TFA or HCl.Alternatively, V may contain an alkyl halide, such as the bromide shown,and reacted with the product of reductive amination (step 2) of aldehydeIV with the amine to form VI (step 3), The alkylation using halide V maybe conducted in the presence of a base, such as NaH, NaOH, Hunig's base,or NaHMDS in a solvent such as TMF or DMF. The halide and nitrosubstituted compounds VI may be reacted with alkyl, aryl, or heteroarylalcohols, thiols, phenols, or thiophenols using a base such as K₂CO₃ orHunig's base in a solvent such as TMF or DMF. Nitro groups may bereduced to amino groups, using Pd or Raney Ni catalysed hydrogenation orusing Fe in the presence of NH₄Cl, HCl, of acetic acid, and furtherfunctionalized to compounds I using the processes described its U.S.Patent Application Publication Nos. 20070232627, 20070197558 and20070232645, and WO2008/133753. T is —CH₂—N(R)—CH₂— or —CH2—NH—CH2—.

In addition, the compounds of formula 1 can be directly prepared from

or an activated derivative thereof. For example, the compounds of thepresent invention can be prepared from a compound of Formula VI as shownin Scheme VII, which can be prepared through Schemes I-V by substitutingchloro and nitro for IV and V. The halide and nitro substitutedcompounds VI may be reacted with alkyl, aryl, or heteroaryl alcohols,thiols, phenols, or thiophenols using a base such as K₂CO₃ or Hunig'sbase in a solvent such as THF or DMF. Nitro groups may be reduced toamino groups, using Pd or Raney Ni catalyzed hydrogenation or using Fein the presence of NH₄Cl, HCl, or acetic acid, and furtherfunctionalized to compounds I using the processes described in U.S.Patent Application Publication Nos. 20070232627, 20070197558 and20070232645, and WO2008/133753.

The compounds having Formulae II and III can be similarly preparedaccording to the above schemes, as appreciated by those skilled in theart.

If a moiety described herein (e.g., —NH₂ or —OH) is not compatible withthe synthetic methods, the moiety may be protected with a suitableprotecting group that is stable to the reaction conditions used in themethods. The protecting group may be removed at a suitable point in thereaction sequence to provide a desired intermediate or target compound.Suitable protecting groups and methods for protecting or deprotoctingmoieties are well know in the art, examples of which can be found isGreene and Wuts, supra. Optimum reaction conditions and reaction timesfor each individual step may vary depending on the particular reactantsemployed and substituents present in the reactants used. Solvents,temperatures and other reaction conditions may be readily selected byone of ordinary skill in the art based on the present invention.

It should be understood that the above-described embodiments and schemesand the following examples are given by way of illustration, notlimitation. Various changes and modifications within the scope of thepresent invention will become apparent to those skilled in the art fromthe present description.

EXAMPLE 14-(4-aminophenylthio)-N′-(4-(4-aminophenylthio)-3-(7-isopropylpyrido[2,3-d]pyrimidin-4-ylamino)benzoyl)-3-(7-isopropylpyrido[2,3-d]pyrimidin-4-ylamino)benzohydrazide

EXAMPLE 1A 4-(4-Amino-phenylsulfanyl)-3-nitro-benzoic acid methyl ester

A mixture of 4-chloro-3-nitrobenzoic acid methyl ester (15.0 g, 68mmol), 4-aminothiophenol (8.8 g, 68 mmol) and K₂CO₃ (11.8 g, 85 mmol) inDMF (150 mL) was heated at 90° C. for 1.5 hours, cooled to roomtemperature, and then poured into H₂O (450 mL) under stirring. Theaqueous mixture was extracted with ethyl acetate (400 mL). The extractwas washed with H₂O (3 times) and brine, dried over MgSO₄, andevaporated to give the crude produce as orange crystal. The crudeproduct was suspended in 150 mL of i-Pr₂O and stirred at roomtemperature for 1 hour. The crystal was collected by filtration, washedwith i-Pr₂O and dried at 60° C. for 3 days under reduced pressure gavepurified title compound as orange crystal (18.6 g, 90% yield).

EXAMPLE 1B 4-(4-tert-Butoxycarbonylamino-phenylfulfanyl)-3-nitro-benzoicacid methyl ester

A solution of the produce from Example 1A (18.5 g, 61 mmol) anddi-tert-butyl dicarbonate (26.8 g, 122 mmol) in p-dioxane (280 mL) washeated at 90° C. for 3 hours. An additional di-tert-butyl dicarbonate(26.8 g, 122 mmol) was added and the mixture was heated at 90° C. for 3hours. A second additional di-tert-butyl bicarbonate (13.4 g, 61 mmol)was added and the mixture was heated at 90° C. for 4 hours. The reactionmixture was cooled to room temperature, and then evaporated. The residuewas diluted with i-Pr₂O (250 mL) and the mixture was stirred at roomtemperature for 1 hour. The resulting crystal was collected byfiltration, washed with i-Pr₂O and dried at 60° C. overnight underreduced pressure gave the title compound as yellow crystal (22.8 g, 93%yield).

EXAMPLE 1C 3-Amino-4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-benzoicacid methyl ester

A suspension of the product from Example 1B (22.8 g, 56 mmol), Fe powder(16.4 g, 282 mmol) and NH₂Cl (15.1 g, 282 mmol) in aqueous BtOH[prepared from EtOH (228 mL) and H2O (228 mL)] was gradually heated toreflux and gently refluxed for 2 hours. The reaction mixture was cooledto room temperature and filtered through celite pad. The filtrate wasevaporated. The aqueous residue was portioned between Ethyl acetate andH2O, made basic to pH 9 with K₂CO₃, and then filtered through celitepad. The organic layer was separated, washed with H₂O and brine, driedover MgSO₄ and evaporated. The oily residue was crystallized in thetreatment with i-Pr₂O (200 mL) and stirred at room temperature for 30minutes. The resulting crystal was collected by filtration, washed withi-Pr₂O and dried as 60° C. overnight under reduced pressure gave thetitle compound as colorless crystal (1.39 g, 66% yield).

EXAMPLE 1D4(4-tert-Butoxycarboylamino-phenylsulfanyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzoicacid methyl ester

A suspension ofN′-(3-cyano-6-isopropyl-pyridin-2-yl)-N-N-dimethyl-formamidine (2.00 g,9.3 mmol) and the product from Example 1C (3.46 g, 4.3 mmol) in AcOH (40mL) was heated at 120° C. for 20 minutes under N₂. After cooing to roomtemperature, the reaction mixture was portioned between ethyl acetate(150 ml) and H₂O (200 mL) and then made basic to pH 9 with K₂CO₃ understirring. The organic layer was separated, washed with 10% NaHCO₃, H₂Oand brine, dried over MgSO₄, and evaporated to give a pale brown oil.The oily residue was separated by silica gel column chromatography(ethyl acetate/n-hexane=5/1) gave yellow crystal. Further purificationby washing with cold ethyl acetate (15 mL) gave the title compound asslightly yellow crystal (3.27 g, 65% yield).

EXAMPLE 1E4-(4-tert-Butoxycarbonylamino-phenylsulfanyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzoicacid

To a solution of the product from Example 1D (3.25 g, 6.0 mmol) in THF(32.5 mL) was added aqueous LiOH [prepared from LiOH monohydrate (1.02g, 24 mmol) and H₂O (10 mL)] dropwise at room temperature. The mixturewas stirred at room temperature for 26 hours, and then evaporated. Theaqueous mixture was diluted with 100 mL of H₂O, washed with ethylacetate (50 mL), and then carefully acidified to pH 4-5 with 10% HCl at5° C. under stirring. The resulting solid was collected by filtration,washed with H₂O, and dried at 60° C. overnight under reduced pressuregave the title compound as pale yellow-crystal (3.09 g, 98% yield).

EXAMPLE 1F tert-butyl4,4′-(4,4′-(hydrazine-1,2-diylbis(oxomethylene))bis(2-(7-isopropylpyrido[2,3-d]pyrimidin-4-ylamino)-4,1-phenylene)bis(sulfanediyl)bis(4,1-phenylene)dicarbamate

To a solution of the product from Example 1E (106 Mg, 0.200 mmol) inDMSO (1.0 mL) at room temperature were added Hunig's base (87 μl, 0.499mmol), hydrazine hydrate (5.0 mg, 0.100mmol), and HATU (118 mg, 0.310mmol) and the reaction was stirred at room temperature overnight.Diluted with water and isolated the solid by filtration. Purification bychromatography on silica gel eluting with 0-10% methanol indichloromethane gave the title compound (50 mg, 4.7% yield).

EXAMPLE 1G4-(4-aminophenylthio)-N′(4-(4-aminophenylthio)-3-(7-isopropylpyrido[2,3-d]pyrimidin-4-ylamino)benzoyl)-3-(7-isopropylpyrido[2,3-d]pyrimidin-4-ylamino)benzohydrazide

The product from Example 1F (50 mg, 0.047 mmol) was dissolved in THF(1.0 mL) and 4 M HCl in dioxane (0.5 m) was added and the reaction wasstirred at room temperature overnight. Collected product by filtration,dissolved in methanol and added to NaHCO₃ solution, and extracted withethyl acetate. Dried over MgSO₄, filtered and evaporated. Purificationby chromatography on silica gel eluting with 0-10% methanol indichloromethane gave the title compound as a yellow solid (6 mg, 15%yield). ¹H NMR (300 MHz, DMSO-D6) δ ppm 1.33 (d, J=6.99 Hz, 12 H)3.16-3.20 (m, 2 H) 5.60 (s, 4 H) 6.63 (d, J=8.46 Hz, 4 H) 6.84 (d,J=8.09 Hz, 2 H) 7.14 (d, J=8.46 Hz, 4 H) 7.63 (d, J=8.46 Hz, 2 H) 7.73(d, J=8.46 Hz, 2 H) 7.87 (s, 2 H) 8.58 (s, 2 H) 8.87 (d, J=8.46 Hz, 2 H)10.13 (s, 2 H) 10.45 (s, 2 H). MS (ESI) m/z 859 (M+H)⁺.

EXAMPLE 24-(4-aminophenylthio)-N-(4-(4-aminophenylthio)-3-(7-isopropylpyrido[2,3-d]pyrimidin-4-ylamino)phenyl)-3-(7-isopropylpyrido[2,3-d]pyrimidin-4-ylamino)benzamide

EXAMPLE 2A tert-butyl4-(4-amino-2-(7-isopropylpyrido[2,3-d]pyrimidin-4-ylamino)phenylthio)phenylcarbamate

To a solution of the product from Example 1E (05 g, 0.941 mmol) in DMSO(5.0 mL) at room temperature were added. Hunig's base (0.493 ml, 2.82mmol), sodium azide (0.153 g, 2.351mmol), and HATU (0.465 g, 1.223 mmol)and the reaction was stirred at room temperature for 1 hour. Thereaction was dilated with ethyl acetate and washed with water and brine.The organic was dried over MgSO₄, filtered and concentrated. The crudeproduct was used without further purification.

A solution of the product from the first step (0.524 g, 0.941 mmol) istoluene (50 ml) was stirred at 100° C. for 30 minutes. The reaction wascooled and 2-(trimethylsilyl)ethanol (1.349 ml, 9.41 mmol) was added andthe mixture was heated at 50° C. for 1.5 hours. The reaction was cooledand evaporated. The crude product used without further purification.

To a solution of the crude product from the second step in THF (9.41 ml)at room temperature was added TBAF (4.71 ml, 4.71 mmol) and the reactionwas stirred at room temperature for 5 hours. The reaction was dilutedwith ethyl acetate and washed with water, and brine. The organic wasdried over MgSO₄, filtered and concentrated. The product was purified bychromatography on silica gel eluting with a gradient starting withdichloromethane and ending with ethyl acetate gave the title compound asa yellow solid (340 mg, 72% yield).

EXAMPLE 2B4-(4-(tert-butoxycarbonylamino)phenylthio)-N-(4-(4-(tert-butoxycarbonylamino)phenylthio)-3-(7-isopropylpyrido[2,3-d]pyrimidin-4-ylamino)phenyl)-3-(7-isopropylpyrido[2,3-d]pyrimidin-4-ylamino)benzamide

To a solution of the product from Example 1E (50 mg, 0.094 mmol) in DMSO(0.5 mL) at room temperature were added Hunig's base (49.3 μl, 0.282mmol), the product from Example 2A (47.3 mg, 0.094 mmol), and HATU (42.9mg, 0.113 mmol) and the reaction was stirred at room temperatureovernight. The reason was diluted with ethyl acetate and washed withwater. The organic was dried ever MgSO₄ filtered and concentrated. Thecrude product was used without further purification.

EXAMPLE 2C4-(4-aminophenylthio)-N-(4-(4-aminophenylthio)-3-(7-isopropylpyrido[2,3-d]pyrimidin-4-ylamino)phenyl)-3-(7-isopropylpyrido[2,3-d]pyrimidin-4-ylamino)benzamide

To a solution of Reactant I (96 mg, 0.094 mmol) in Dichloromethane (2ml) at rt was added TFA (2 ml) and the reaction was stirred at rt for 30minutes. The reaction was evaporated.

The crude product was added to a reverse phase column and was elutedwith a gradient starting with 5% acetonitrile in water (0.1% TFA) andending with 75% acetonitrile in water (0.1% TFA). Most of the solventwas evaporated. Extracted with ethyl acetate and washed with saturatedNaHCO₃. Dry MgSO₄, filtered, evaporated and concentrated to give thetitle compound (15.7 mg, 20% yield). ¹H NMR (300 MHz, DMSO.D6) δ ppm1.33 (d, J=6.62 Hz, 12 H) 3.12-3.27 (m, 2 H) 5.43 (s, 2 H) 5.59 (s, 2 H)6.54 (d, J=8.46 Hz, 2H) 6.63 (d, J=8.82 Hz, 2 H) 6.87 (d, J=8.46 Hz, 1H) 6.92 (d, J=8.82 Hz, 1 H) 7.06 (d, J=8.46 Hz, 2 H) 7.13 (d, J=8.46 Hz,2 H) 7.52-7.66 (m, 3 H) 7.78 (d, J=8.09 Hz, 1 H) 7.88 (d, J=2.21 Hz, 1H) 7.94 (s, 1 H) 8.55 (s, 1 H) 8.58 (s, 1 H) 8.84 (d, J=8.82 Hz, 1 H)8.87 (d, J=8.46 Hz, 1 H) 10.04 (s, 1 H) 10.16 (s, 1 H) 10.27 (s, 1 H).MS (ESI) m/z 816 (M+H)⁺.

EXAMPLE 31,3-bis(4-(4-aminophenylthio)-3-(7-isopropylpyrido[2,3-d]pyrimidin-4-ylamino)phenyl)urea

EXAMPLE 3A tert-butyl4,4′-(4,4′-carbonylbis(azanediyl)bis(2-(7-isopropylpyrido[2,3-d]pyrimidin-4-ylamino)-4,1-phenylene))bis(sulfanediyl)bis(4,1-phenylene)dicarbamate

To a solution of the product from Example 1E (0.05 g, 0.094 mmol) inDMSO (0.5 mL) at room temperature were added Hunig's base (0.049 ml,0.282 mmol), sodium azide (0.015 g, 0.235 mmol), and HATU (0.046 g,0.122 mmol) and the reaction was stirred at room temperature for 1 hour.The reaction was diluted with ethyl acetate and washed with water (2×)and brine. The organic was dried over MgSO4, filtered and concentrated.The crude product was used without further purification.

A solution of the product from the first step (0.052 g, 0.094 mmol) intoluene (4.70 ml) was stirred at 100° C. for 30 minutes. The reactionwas cooled and evaporated. THF (1 mL) and the product from Example 2A(0.047 g, 0.094 mmol) were added and the mixture was heated at 50° C.for 1.5 hours. The reaction was cooled and evaporated to give the titlecompound which was used without further purification.

EXAMPLE 3B1,3-bis(4-(4-aminophenylthio)-3-(7-isopropylpyrido[2,3-d]pyrimidin-4-ylamino)phenyl)urea

To a solution of the product from Example 3A (97 mg, 0.094 mmol) indichloromethane (1 mL) at room temperature was added TFA (1 mL) and thereaction was stirred at room temperature for 30 minutes. The reactionwas evaporated. Purification by reverse phase (C18) chromatographyeluting with a gradient starting with 95:5 water (0.1% TFA):acetonitrileand ending with 1:1 water (0.1% TFA):acetonitrile. Most of the solventwas evaporated. Extracted with ethyl acetate and washed with saturatedNaHCO₃. Dry MgSO₄, filtered, evaporated and concentrated to give thetitle compound (35.5 mg, 45% yield). ¹H NMR (300 MHz, DMSO-D6) δ ppm1.33 (d, J=6.90 Hz, 6 H) 3.13-3.29 (m, 1 H) 5.38 (s, 2 H) 6.51 (d,J=8.46 Hz, 2 H) 0.94 (d, J=8.46 Hz, 1 H) 7.03 (d, J=8.46 Hz, 2 H) 7.23(dd, J=8.82, 2,21 Hz, 1 H) 7.00 (d, J=8.82 Hz, 1 H) 7.66 (d, J=2.21 Hz,1 H) 8.55 (s, 1 H) 8.74-8.92 (m, 2 H) 9.97 (s, 1 H), MS (ESI) m/z 831(M+H)⁺.

EXAMPLE 44,4′-(4-amino-phenylsulfanyl)-N*3*,N*3″*-(7-isopropylpyrido[2,3-d]pyrimidin-4-yl)-[1,1′;4′,1″]terphenyl-3,3″-diamine

EXAMPLE 4A 4,4″-Dichloro-3,3″-dinitro-[1,1′;4′,1″]terphenyl

1,4-diiodobenzene (200 mg, 0.606 mmol), 4-chloro-5-nitrophenylboronicacid (256 mg, 1.273 mmol), and Pd(PPh₃)₄ (35 mg, 0.03 mmol), were addedto a flask followed by Na₂CO₃ (321 mg, 3.03 mmol). DMF (6.0 mL) andwater (1.0 mL) were added and the mixture was bubbled with N₂ for tenminutes. Heated solution to 110° C. for 30 min in a microwave reactor. Alarge amount of precipitate formed. Water and dichloromethane were addedand the mixture was extracted with dichloromethane. Dried over MgSO₄,filtered and concentrated to give the title compound as a light brownsolid. (250 mg), which was used without further purification.

EXAMPLE 4B4,4″-(4-amino-phenylsulfanyl)-3,3″-dinitro-[1,1′;4′,1″]terphenyl

To a solution of the product from Example 4A (250 mg, 0.642 mmol) in DMF(3.0 mL) were added 4-aminobenzenethio (161 mg, 1.285 mmol) andpotassium carbonate (266 mg, 1.927 mmol) and the mixture was heated to90° C. for 1.5 hours and then stirred at room temperature overnight. Themixture was extracted with dichloromethane and washed with water. Aprecipitate formed in the dichloromethane extract solution and thisbrown solid was collected by filtration and air dried to provide thetitle compound (90 mg, 25% yield).

EXAMPLE 4C4,4″-(4-tert-butoxycarbonylamino-phenylsulfanyl)-3,3″-dinitro-[1,1′;4′,1″]terphenyl

The product from Example 4B (75 mg, 0.132 mmol) was suspended in dioxane(4.0 mL) and di-tert-butyl dicarbonate was added (100 mg, 0.457 mmol)and the mixture was heated to 90° C. After 2 hours, more di-tert-butylbicarbonate (100 mg, 0.867 mmol) was added and the mixture was heated at90° C. overnight. The reaction was evaporated to give the title compoundas a brown semi-solid, which was used without further purification.

EXAMPLE 4D 4,4″-(4-tert-butoxycarbonylamino-phenylsulfanyl)-[1,1′;4′,1″]terphenyl-3,3″-diamine

To a suspension of the product from Example 4C (100 mg, 0.130 mmol) inTHF (2.0 mL), EtOH (2.0 mL), and water (0.6 mL) mixture were added Fe(72.8 mg, 1.304 mmol) and ammonium chloride (34.9 mg, 0.652 mmol) andthe mixture was heated at 90° C. for 1.5 hours. DMF was added and themixture was heated to 50-60° C. and the mixture was filtered and solidswere rinsed with warm DMF. Then DMF nitrate was evaporated to a brownsemi-solid. The solid was extracted with ethyl acetate and washed withwater. Dried over MgSO₄, filtered and evaporated to yield the titlecompound as a brown solid (90 mg) and the product was used withoutfurther purification.

EXAMPLE 4E4,4″-(4-tert-butoxycarbonylamino-phenylsulfanyl)-N*3*,N*3″*-(7-isopropylpyrido[2,3-d]pyrimidin-4-yl)-[1,1′;4′,1″]terphenyl-3,3″-diamine

To a suspension of the product, from Example 4D (80 mg, 0.113 mmol) inAcOH (3.0 mL) was added(E)-4′(3-cyano-6-isopropylpyridin-2-yl)-N,N-dimethylformimidamide (53.8mg, 0.249 mmol) and the mixture was placed into a preheated oil bath at120° C. for 15 minutes. The reaction was cooled and the mixture wasextracted with dichloromethane and washed with saturated Na₂CO₃. Driedover MgSO₄, filtered and evaporated to yield the title compound as abrown solid (110 mg) and the produce was used without furtherpurification.

EXAMPLE 4F 4,4″-(4-amino-phenylsulfanyl)-N*3*,N*3%41*-(7-isopropylpyrido[2,3-d]pyrimidin-4-yl-[1,1′;4′,1″]terphenyl-3,3″-diamine

The product of Example 4E (110 mg, 0.105 mmol) was dissolved indichloromethane (0.3 mL) and TFA (2.7 mL) and the solution was stirredat room temperature for 30 minutes. The solvent was evaporated and theresidue was extracted with 30% MeOH in dichloromethane and washed with1N Na₂CO₃. Dried over MgSO₄, filtered and evaporated. Purification bychromatography on silica gel eluting with 0-10% MeOH in dichloromethanegave the title compound as a light yellow solid (22 mg, 25% yield). 1HNRM (300 MHz, DMSO-d₆): δ 10.10 (s, 2 H), 8.88 (d, J=8.1 Hz, 2 H), 8.56(s, 2 H), 7.78 (m, 2 H), 7.73 (s, 4 H), 7.61 (m, 4 H), 7.14 (d, J=8.5Hz, 4 H), 6.91 (d, J=7.7 Hz, 2 H), 6.61 (d, J=8.2 Hz, 4 H), 5.53 (s, 4H), 3.20 (m, 2 H), 1.34 (d, J=7.0 Hz, 12 H). MS (ESI) m/z 849 (M+H)^(+.)

EXAMPLE 5N,N′-(ethane-1,2-diyl)bis(4-(4-aminophenylthio)-3-(7-isopropylpyrido[2,3-d]pyrimidin-4-ylamino)benzamide)

EXAMPLE 5A tert-butyl4,4′-(4,4′-(ethane-1,2-diylbis(azanediyl))bis(oxomethylene)bis(2-(7-isopropylpyrido[2,3-d]pyrimidin-4-ylamino)-4,1-phenylene))bis(sulfanediyl)bis(4,1-phenylene)dicarbamate

To a solution of the product from Example 1E (50 mg, 0.094 mmol) in DMSO(2.0 mL) were added ethylenediamine (6.4 μL, 0.095 mmol), HATU (39.5 mg,0.104 mmol), Hunig's base (50 μL, 0.282 mmol), and the mixture wasstirred at room temperature until the starting material was consumed.Additional product from Example 1E (50 mg, 0.094 mmol), HATU (39.5 mg,0.104 mmol), and Hunigs base (50 μL, 0.282 mmol) were added and thereaction was stirred for 2 hours. The reaction was diluted with ethylacetate and washed with HCl (aq. 1M). Dried over Na₂SO₄, filtered andevaporated. Purification by chromatography on silica gel eluting with(4% to 7% methanol in dichloromethane) gave the title compound (100 mg,91% yield) as a light yellow solid. ¹H NMR (500 MHz, DMSO-D6) δ ppm 1.32(d, J=6.87 Hz, 12 H) 1.46 (s, 18 H) 3.39 (s, 4 H) 6.94 (d, J=8.09 Hz, 2H) 7.30 (d, J=8.70 Hz, 4 H) 7.48 (d, J=8.54 Hz, 4 H) 7.59 (d, J=8.09 Hz,2 H) 7.66 (d, J=8.09 Hz, 2 H) 7.84 (s, 2 H) 8.54 (s, 2 H) 8.56 (s, 2 H)8.81 (d, J=8.39 Hz, 2 H) 9.53 (s, 2 H) 10.12 (s, 2 H). MS (ESI) m/z 1088(M+H)⁺.

EXAMPLE 5BN,N′-(ethane-1,2-diyl)bis(4-(4-aminophenylthio)-3-(7-isopropylpyrido[2,3-d]pyrimidin-4-ylamino)benzamide)

The product from Example 5A was dissolve in dichloromethane (2.0 mL) andTFA (2.0 mL) and the mixture was stirred at room temperature for 1 hour.The solvent was evaporated and NH₄OH was added and the mixture wasevaporated to dryness. Purification by prep TLC (10% methanol indichloromethane) gave the title compound (28 mg, 36% yield) as a yellowsolid. ¹H NMR (300 MHz, DMSO-d6) δ ppm 1.32 (d, J=6.99 Hz, 12 H) 5.55(s, 4 H) 6.60 (d, J=8.46 Hz, 4 H) 6.75 (d, J=8.09 Hz, 2 H) 7.10 (d,J=8.46 Hz, 4 H) 7.57 (s, 4 H) 7.76 (s, 2 H) 8.50 (s, 4 H) 8.80 (d,J=5.52 Hz, 2 H). MS (ESI) m/z 888 (M+H)⁺.

EXAMPLE 6piperazine-1,4-diylbis((4-(4-aminophenylthio)-3-(7-isopropylpyrido[2,3-d]pyrimidin-4-ylamino)phenyl)methanone)

EXAMPLE 6A tert-butyl4-(2-(7-isopropylpyrido[2,3-d]pyrimidin-4-ylamino)-4-piperazine-1-carbonyl)phenylthio)phenylcarbamate

To a solution of the product from Example 1E (100 mg, 0.188 mmol) inDMSO (2.0 mL) were added piperazine (16 mg, 0.188 mmol), HATU (79 mg,0.207 mmol) and Hunigs base (100 μL, 0.564 mmol) and the mixture wasstored at room temperature until the starting material was consumed.Additional product from Example 1E (100 mg, 0.188 mmol), HATU (79 mg,0.212 mmol), and Hunigs base (100 μL, 0.564 mmol), were added and thereaction was stirred for 2 hours. The reaction was diluted with ethylacetate and washed water. Dried over Na₂SO₄, filtered and evaporated.Purification by chromatography on silica gel eluting with (10% methanolin dichloromethane) gave the title compound (150 mg) as a yellow solid.

EXAMPLE 6B tert-butyl4,4′-(4,4′-(piperazine-1,4-diylbis(oxomethylene))bis(2-(7-isopropylpyrido[2,3-d]pyrimidin-4-ylamino)-4,1-phenylene))bis(sulfanediyl)bis(4,1-phenylene)dicarbamate

To a solution of the product from Example 6A (20 mg, 0.033 mmol) in DMF(1.0 mL) and pyridine (1.0 mL) were added EDAC (32 mg, 0.167 mmol) andthe product from Example 1E (17.7 mg, 0.033 mmol) and the mixture wasstored at room temperature overnight. The solvent was evaporated and theresidue was suspended in methanol. The solid was collected usingcentrifugation gave the title compound (22 mg, 57% yield).

EXAMPLE 6Cpiperazine-1,4-diylbis((4-(4-aminophenylthio)-3-(7-isopropylpyrido[2,3-d]pyrimidin-4-ylamino)phenyl)methanone)

The product from Example 6B was dissolved in TFA (1.0 mL) anddichloromethane (1.0 mL) and the mixture was then allowed to stir atroom temperature for 1 hour. The solvent was evaporated and NH₄OH wasadded and the mixture was evaporated to dryness. Purification byprecipitation from methanol gave the title compound (12 mg, 94% yield)as a yellow solid. ¹H NMR (300 MHz, DMSO-D6) δ ppm 1.32 (d, J=6.62 Hz,12 H) 3.14-3.24 (m, 2 H) 3.54 (s, 8 H) 5.60 (s, 4 H) 6.61 (d, J=8.46 Hz,4 H) 6.79 (d, J=5.15 Hz, 2 H) 7.13 (d, J=8.46 Hz, 4 H) 7.23 (s, 2 H)7.41 (s, 2 H) 7.61 (d, J=6.99 Hz, 2 H) 8.56 (s, 2 H) 8.84 (d, J=6.25 Hz,2 H) 10.11 (s, 2 H). MS (ESI) m/z 914 (M+H)^(+.)

EXAMPLE 7N-(4-(4-aminophenylthio)-3-(7-isopropylpyrido[2,3-d]pyrimidin-4-ylamino)phenyl-3-(7-isopropylpyrido[2,3-d]pyrimidin-4-ylamino)benzamide

EXAMPLE 7A methyl3-(7-isopropylpyrido[2,3-d]pyrimidin-4-ylamino)benzoate

To methyl 3-aminobenzoate (0.50 g, 3.31 mmol) in acetic acid (10 mL) wasadded (E)-N′-(3-cyano-6-isopropylpyridin-2-yl)-N,N-dimethylformimidamide(0.71 g, 3.31 mmol) and the mixture was stirred at 120° C. for 25minutes. Reaction mixture was cooled to room temperature and a solidformed. Water was added and solid was collected by filtration.Purification by chromatography on silica gel eluting with 0-30% methanolin dichloromethane gave the title compound (1.05 g, 98% yield).

EXAMPLE 7B 3-(7-isopropylpyrido[2,3-d]pyrimidin-4-ylamino)benzoic acid

The product from Example 7A (1.0 g, 3.26 mmol) was dissolved in THF(12.0 mL) and water (12.0 mL) and LiOH (390 mg, 16.29 mmol) was addedand the reaction was stirred at room temperature overnight. Reaction wasneutralised with 1 N HCl and extracted with ethyl acetate. Dried overNa₂SO₄, filtered and concentrated to give the title compound (1.5 g).

EXAMPLE 7C tert-butyl4-(2-(7-isopropylpyrido[2,3-d]pyrimidin-4-ylamino)-4-(3-(7-isopropylpyrido[2,3-d]pyrimidin-4-ylamino)benzamido)phenylthio)phenylcarbamate

To a solution of the product from Example 7B (25.8 mg, 0.084 mmol) inDMSO (2.0 mL) were added the product from Example 2A (40 mg, 0.084mmol), HATU (31.8 mg, 0.084 mmol), and Hunigs base (56 μL, 0.318 mmol),and the mixture was stirred at room temperature for 24 hours. AdditionalHATU (39.5 mg, 0.104 mmol), and Hunigs base (50 μL, 0.282 mmol) wereadded and the reaction was stirred for 48 hours. Added more HATU (39.5mg, 0.104 mmol) and heated at 45° C. for 8 hours. Added more HATU (39.5mg, 0.104 mmol) and stirred overnight at room temperature. Water wasadded and the product was collected by filtration. Purification bychromatography on silica gel eluting with (0% to 5% methanol indichloromethane) gave the title compound (40 mg, 63% yield).

EXAMPLE 7DN-(4-(4-aminophenylthio)-3-(7-isopropylpyrido[2,3-d]pyrimidin-4-ylamino)phenyl)-3-(7-isopropylpyrido[2,3-d]pyrimidin-4-ylamino)benzamide

The product from Example 7C (40 mg, 0.050 mmol) was dissolved in dioxane(2.0 mL) and 4M HCl in dioxane (0.25 mL) was added. This solution wasstirred at room temperature overnight. The solid HCl salt of the productwas filtered off then dissolved in methanol and added to saturatedNaHCO₃. Extracted with ethyl acetate and evaporated. Purification bychromatography on silica gel eluting with (0% to 30% methanol indichloromethane) gave the title compound (13 mg, 37% yield). ¹H NMR (300MHz, DMSO-D6) d ppm 1.36 (dd, J=6.80, 4.23 Hz, 12 H) 3.20-3.30 (m, 2 H)6.57 (d, J=8.46 Hz, 2 H) 7.04-7.12 (m, 3 H) 7.60-7.70 (m, 2 H) 7.82-7.95(m, 3 H) 8.00-8.08 (m, 2 H) 8.29 (s, 1H) 8.83-8.93 (m, 2 H) 9.09 (d,J=12.50 Hz, 1 H) 9.17 (d, J=7.72 Hz, 1 H) 10.58 (s, 1 H) 11.38 (s, 1 H)11.69 (s, 1 H). MS (ESI) m/z 693 (M+H)^(+.)

EXAMPLE 8N,N′-(5,5′-(ethyne-1,2-diyl)bis(2-(4-aminophenylthio)-5,1-phenylene))bis(7-isopropylpyrido[2,3-d]pyrimidin-4-amine)

The title compound can be prepared by first coupling1-fluoro-4-iodo-2-nitrobenzene with ethynyltrimethylsilane bySonogashira reaction using a suitable catalyst. Pd catalysts such asPd(PPh₃)₄ or Pd(dppf)Cl₂ may be employed or generated in situ using a Pd(II) catalyst such Pd(OAc)₂ or Pd₂(dba)₃ and organosphosphorous ligands,such as PPh₃ or P(t-Bu)₃. Alternatively, a Cu (I) catalyst may beemployed, such as Cu (I) iodide. Reactions may be conducted withaddition of a base such K₂CO₃ or K₃PO₄ or an amine base such astriethylamine or Hunig's base in a solvent such as THF or DMF. Thetrimethylsilyl (TMS) protecting group may be removed using a base suchas K₃CO₃ in a solvent such as methanol or THF to produce4-ethynyl-1-fluoro-2-nitrobenzene. A second Sonogashira reaction between1-fluoro-4-iodo-2-nitrobenzene and 4-ethynyl-1-fluoro-2-nitrobenzene maybe conducted under the analogous conditions to the first coupling toform 1,2-bis(4-fluoro-3-nitrophenyl)ethyne. Couplings may be conductedconcurrently to give symmetric products or sequentially to givenon-symmetric products. The fluoride and nitro substituted product maybe reacted with alkyl, aryl or heteroaryl alcohols, thiols, phenols, orthiophenols using a base such as K₂CO₃ or Hunig's base in a solvent suchas THF or DMF. Nitro groups may be reduced to amino groups, using Pd orRaney Ni catalysed hydrogenation or using Fe in the presence of NH₄Cl,HCl, or acetic acid, and further functionalized to the title compoundusing the processes described in U.S. Patent Application PublicationNos. 20070232627, 20070197558 and 20070232645, and WO2008/133753.Similarly, 1-chloro-4-iodo--nitrobenzene may be used as the startingmaterial to prepare the title compound of this Example.

The following compounds were also prepared according to the processesdescribed herein:

In addition, the following compounds can be prepared according to thepresent invention:

Likewise, the following compounds of Formula I can be similarly preparedaccording to the present invention,

wherein

are each independently selected from Table 1; —X₁—R₇ and —X₂—R₈ are eachindependently selected from Tablet 2; A₁ and A₂ are each independentlyselected from Table 3, or A₁ is selected from Table 3a and A₂ isselected from Table 3b; and T is selected from Table 4.

TABLE 1

TABLE 2 —X₁—R₇ and —X₂—R₈

TABLE 3 A₁ and A₂

TABLE 3a A₁

TABLE 3b A₂

TABLE 4 —T—

Likewise, the compounds in Table 5 can be prepared according to thepresent invention:

TABLE 5

The inhibitory activities of the compounds of the present invention canbe evaluated using a variety of assays known in the art. For instance,two stable subgenomic replicon cell lines can be used for compoundcharacterization in cell culture: one derived from genotype 1a-H77 andthe other derived from genotype 1b-Con1. The replicon constructs can bebieistronic subgenomic replicons. The genotype 1a replicon constructcontains NS3-NS5B coding region derived from the H77 strain of HCV(1a-H77). The replicon also has a firefly luciferase reporter and aneomycin phosphotransferase (Neo) selectable marker. These two codingregions, separated by the FMDV 2a protease, comprise the first cistronof the bieistronic replicon construct, with the second cistroncontaining the NS3-NS5B coding region with addition of adaptivemutations. The 1b-Con1 replicon construct is identical to the 1a-H77replicon, except that the NS3-NS5B coding region is derived from the1b-Con1 strain and that the replicon contains different adaptivemutations. Replicon cell lines can be maintained in Dulbecco's modifiedEagles medium (DMEM) containing 10% (v/v) fetal bovine serum (FBS), 100IU/ml penicillin, 100 mg/ml streptomycin (Invitrogen) and 200 mg/ml G418(Invitrogen).

The inhibitory effects of the compounds of the invention on HCVreplication can be determined by measuring activity of the luciferasereporter gene. For example, replicon-containing cells can be seeded into96 well plates at a density of 5000 cells per well in 100 μl DMEMcontaining 5% FBS. The following day compounds can be diluted indimethyl sulfoxide (DMSO) to generate a 200× stock in a series of eighthalf-log dilutions. The dilution series can then be further diluted100-fold in the medium containing 5% FBS. Medium with the inhibitor isadded to the overnight cell culture plates already containing 100 μl ofDMEM with 5% FBS. In assays measuring inhibitory activity in thepresence of human plasma, the medium from the overnight cell cultureplates can be replaced with DMEM containing 40% human plasma and 5% FBS.The cells can be incubated for three days in the tissue cultureincubators and are then lysed for RNA extraction. For the luciferaseassay, 30 μl of Passive Lysis buffer (Promega) can be added to eachwell, and then the plates are incubated for 15 minutes with rocking tolyse the cells. Lyciferin solution (100 μl, Promega) can be added toeach well, and luciferase activity can be measured with a Victor IIluminometer (Perkin-Elmer). The percent inhibition of HCV RNAreplication can be calculated for each compound concentration and theIC₅₀ and/or EC₅₀ value can be calculated using nonlinear regressioncurve fitting to 4-parameter logistic equation and GraphPad Prism 4software.

When evaluated using the above method, representative compounds of thepresent invention inhibited HCV replicon replication with IC₅₀ values inthe range of from about 0.1 nM to about 100 μM. IC₅₀ refers to 50%inhibitory concentration. Cytotoxicity of the compounds of the presentinvention can also be evaluated using methods known in the art. Whentested, the TC₅₀ values of representative compounds of the presentinvention were often greater than the corresponding IC₅₀ values of thecompounds. TC₅₀ refers to 50% toxicity concentration. Table 6 lists theIC₅₀ values of the compounds of Examples 1-28 when tested using HCVreplicons.

TABLE 6 Example IC₅₀ for replicon 1b-Con1 1 0.1 nM-10 nM 2 0.1 nM-10 nM3   10 nM-100 nM 4 0.1 nM-10 nM 5 0.1 nM-10 nM 6 0.1 nM-10 nM 7 100nM-10 μM  8 less than 0.1 nM 9 less than 0.1 nM 10 100 nM-10 μM  11 0.1nM-10 nM 12 0.1 nM-10 nM 13 0.1 nM-10 nM 14 0.1 nM-10 nM 15 0.1 nM-10 nM16 0.1 nM-10 nM 17 0.1 nM-10 nM 18 0.1 nM-10 nM 19 0.1 nM-10 nM 20 0.1nM-10 nM 21 0.1 nM-10 nM 22   10 nM-100 nM 23 0.1 nM-10 nM 24 0.1 nM-10nM 25 0.1 nM-10 nM 26 0.1 nM-10 nM 27 0.1 nM-10 nM 28   10 nM-100 nM

The present invention also features pharmaceutical compositionscomprising the compounds of the invention. A pharmaceutical compositionof the present invention can comprise one or more compounds of theinvention, each of which has a formula independently selected fromselected from Formulae I, II or III.

In addition, the present invention features pharmaceutical compositionscomprising pharmaceutically acceptable salts, solvates, or prodrugs ofthe compounds of the invention. Without limitation, pharmaceuticallyacceptable salts can be zwitterions or derived from pharmaceuticallyacceptable inorganic or organic acids or bases. Preferably, apharmaceutically acceptable salt retains the biological effectiveness ofthe free acid or base of the compound without undue toxicity,irritation, or allergic response, has a reasonable benefit/risk ratio,is effective for the intended use, and is not biologically or otherwiseundesirable.

The present invention further features pharmaceutical compositionscomprising a compound of the invention (or a salt, solvate or prodrugthereof) and another therapeutic agent. By way of illustration notlimitation, these other therapeutic agents can be selected fromantiviral agents (e.g., anti-HIV agents, anti-HBV agents, or otheranti-HCV agents such as HCV protease inhibitors, HCV polymeraseinhibitors, HCV helicase inhibitors, IRES inhibitors or NSSAinhibitors), antibacterial agents, anti-fungal agents, immunomodulators,anti-cancer or chemotherapeutic agents, anti-inflammation agents,antisense RNA, siRNA, antibodies, or agents for treating cirrhosis orinflammation of the liver. Specific examples of these other therapeuticagents include, but are not limited to, ribavirin, α-interferon,β-interferon, pegylated interferon-α, pegylated interferon-lambda,ribavirin, viramidine, R-5158, nitazoxanide, amantadine, Debio-025,NIM-811, R7128, R1626, R4048, T-1106, PSI-7851, PF-00868554, ANA-598,IDX184, IDX102, IDX375, GS-9190, VCH759, VCH-916, MK-3281, BCX-4678,MK-3281, VBY708, ANA598, GL59728, GL60067, BMS-790052, BMS-791325,BMS-650032, GS-9132, ACH-1095, AP-H005, A-831, A-689, AZD2836,telaprevir, boceprevir, ITMN-191, BI-201335, VBY-376, VX-500 (Vertex),PHX-B, ACH-1625, IDX136, IDX316, VX-813 (Vertex), SCH 900518(Schering-Plough), TMC-435 (Tibotec), ITMN-191 (Intermune, Roche),MK-7009 (Merck), IDX-P1 (Novartis), BI-201335 (Boehringer Ingelheim),R7128 (Roche), PSI-7851(Pharmasset), MK-3281 (Mercke), PF-868554(Pfizer), IDX-184 (Novartis), IDX-375 (Pharmasset), BILB-1941(Boehringer Ingelheim), GS-9190 (Gilead), BMS-790052 (BMS), Albuferon(Novartis), ritonavir, another cytochrome P450 monooxygenase inhibitor,or any combination thereof

In one embodiment, a pharmaceutical composition of the present inventioncomprises one or more compounds of the present invention (or salts,solvates or prodrugs thereof), and one or more other antiviral agents.

In another embodiment, a pharmaceutical composition of the presentinvention comprises one or more compounds of the present invention (orsalts, solvates or prodrugs thereof), and one or more other anti-HCVagents. For example, a pharmaceutical composition of the presentinvention can comprise a compounds of the present invention havingFormula I, II or III (or (or a salts, solvate or prodrug thereof), andan agent selected from HCV polymerase inhibitors (including nucleosideor non-nucleoside type of polymerase inhibitors), HCV proteaseinhibitors, HCV helicase inhibitors, CD81 inhibitors, cyclophilininhibitors, IRES inhibitors, or NS5A inhibitors.

In yet another embodiment, a pharmaceutical composition of the presentinvention comprises one or more compounds of the present invention (orsalts, solvates or prodrugs thereof), and one or more other antiviralagents, such as anti-HIV agents, or anti-hepatitis A, anti-hepatitis D,anti-hepatitis E or anti-hepatitis G agents. Non-limiting examples ofanti-HBV agents include adefovir, lamivudine, and tenofovir.Non-limiting examples of anti-HIV drugs include ritonavir, lopinavir,indinavir, nelfinavir, saquinavir, amprenavir, atazanavir, tipranavir,TMC-114, fosamprenavir, zidovudine, lamivadine, didanosine, stavudine,tenofovir, zalcitabine, abacavir, efavirenz, nevirapine, delavirdine,TMC-125, L-870812, S-1360, enfuvirtide, T-1249, or other HIV protease,reverse transcriptase, integrase or fusion inhibitors. Any otherdesirable antiviral agents can also be included in a pharmaceuticalcomposition of the present invention, as appreciated by those skilled inthe art.

A pharmaceutical composition of the present invention typically includesa pharmaceutically acceptable carrier or excipient. Non-limitingexamples of suitable pharmaceutically acceptable carriers/excipientsinclude sugars (e.g., lactose, glucose or sucrose), starches (e.g., cornstarch or potato starch), cellulose or its derivatives (e.g., sodiumcarboxymethyl cellulose, ethyl cellulose or cellulose acetate), oils(e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil,corn oil or soybean oil), glycols (e.g., propylene glycol), bufferingagents (e.g., magnesium hydroxide or aluminum hydroxide), agar, alginicacid, powdered tragacanth, malt, gelatin, talc, cocoa butter,pyrogen-free water, isotonic saline, Ringer's solution, ethanol, orphosphate buffer solutions. Lubricants, coloring agents, releasingagents, coating agents, sweetening, flavoring or performing agents,preservatives, or antioxidants can also be included in a pharmaceuticalcomposition of the present invention.

The pharmaceutical compositions of the present invention can beformulated based on their routes of administration using methods wellknown in the art. For example, a sterile injectable preparation can beprepared as a sterile injectable aqueous or oleagenous suspension usingsuitable dispersing or wetting agents and suspending agents.Suppositories for rectal administration can be prepared by mixing drugswith a suitable nonirritating excipient such as cocoa butter orpolyethylene glycols which are solid at ordinary temperatures but liquidat the rectal temperature and will therefore melt in the rectum andrelease the drugs. Solid dosage forms for oral administration can becapsules, tablets, pills, powders or granules. In such solid dosageforms, the active compounds can be admixed with at least one inertdiluent such as sucrose lactose or starch. Solid dosage forms may alsocomprise other substances in addition to inert diluents, such aslubricating agents. In the case of capsules, tablets and pills, thedosage forms may also comprise buffering agents. Tablets and pills canadditionally be prepared with enteric coatings. Liquid dosage forms fororal administration can include pharmaceutically acceptable emulsions,solutions, suspensions, syrups or elixirs containing inert diluentscommonly used in the art. Liquid dosage forms may also comprise wetting,emulsifying, suspending, sweetening, flavoring, or perfuming agents. Thepharmaceutical compositions of the present invention can also beadministered in the form of liposomes, as described in U.S. Pat. No.6,703,403. Formulation of drugs that are applicable to the presentinvention is generally discussed in, for example, Hoover, John E.,REMINGTON's PHARMACEUTICAL SCIENCES (Mack Publishing Co., Easton, Pa.:1975) and Lachman, L., eds., PHARMACEUTICAL DOSAGE FORMS (Marcel Decker,New York, N.Y., 1980).

Any compound described herein, or a pharmaceutically acceptable saltthereof, can be used to prepared pharmaceutical compositions of thepresent invention.

The present invention further features methods of using the compounds ofthe present invention (or salts, solvates or prodrugs thereof) toinhibit HCV replication. The methods comprise contacting cells infectedwith HCV virus with an effective amount of a compound of the presentinvention (or a salt, solvate or prodrug thereof), thereby inhibitingthe replication of HCV virus in the cells. As used herein, “inhibiting”means significantly reducing, or abolishing, the activity beinginhibited (e.g., viral replication). In many cases, representativecompounds of the present invention can reduce the replication of HCVvirus (e.g., in an HCV replicon assay as described above) by at least10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more.

The compounds of the present invention may inhibit all HCV subtypes.Examples of HCV subtypes that are amenable to the present inventioninclude, but are not be limited to, HCV genotypes 1, 2, 3, 4, 5 and 6,including HCV genotypes 1a, 1b, 2a, 2b, 2c or 3a. In one embodiment, acompound or compounds of the present invention (or salts, solvates orprodrugs thereof) are used to inhibit the replication of HCV genotype1a. In another embodiment, a compound or compounds of the presentinvention (or salts, solvates or prodrugs thereof) are used to inhibitthe replication of HCV genotype 1b. In still another embodiment, acompound or compounds of the present invention (or salts, solvates orprodrugs thereof) are used to inhibit the replication of both HCVgenotypes 1a and 1b.

The present invention also features methods of using the compounds ofthe present invention (or salts, solvates or prodrugs thereof) to treatHCV infection. The methods typically comprise administering atherapeutic effective amount of a compound of the present invention (ora salt, solvate or prodrug thereof), or a pharmaceutical compositioncomprising the same, to an HCV patient, thereby reducing the HCV virallevel in the blood or liver of the patient. As used herein, the term“treating” refers to reversing, alleviating, inhibiting the progress of,or preventing the disorder or condition, or one or more symptoms of suchdisorder or condition to which such term applies. The term “treatment”refers to the act of treating. In one embodiment, the methods compriseadministering a therapeutic effective amount of two or more compounds ofthe present invention (or salts, solvates or prodrugs thereof), or apharmaceutical composition comprising the same, to an HCV patient,thereby reducing the HCV viral level in the blood or liver of thepatient.

A compound of the present invention (or a salt, solvate or prodrugthereof) can be administered as the sole active pharmaceutical agent, orin combination with another desired drug, such, as other anti-HCVagents, anti-HIV agents, anti-HBV agents, anti-hepatitis A agents,anti-hepatitis D agents, anti-hepatitis E agents, anti-hepatitis Gagents, or other antiviral drugs, Any compound described herein, or apharmaceutically acceptable salt thereof, can be employed in the methodsof the present invention.

A compound of the present invention (or a salt, solvent or prodrugthereof) can be administered to a patient in a single dose or divideddoses. A typical daily dosage can range, without limitation, from 0.1 to200 mg/kg body weight, such as from 0.25 to 100 mg/kg body weight.Single dose compositions can contain these amounts or submultiplesthereof to make up the daily dose. Preferably, each dosage contains asufficient amount of a compound of the present invention that iseffective in reducing the HCV viral load in the blood or liver of thepatient. The amount of the active ingredient, or the active ingredientsthat are combined, to produce a single dosage form may vary dependingupon the host treated and the particular mode of administration, it willbe understood that the specific dose level for any particular patientwill depend upon a variety of factors including the activity of thespecific compound employed, the age, body weight, general health, sex,diet, time of administration, route of administration, rate ofexcretion, drug combination, and the severity of the particular diseaseundergoing therapy.

The present invention further features methods of using thepharmaceutical compositions of the present invention, to treat HCVinfection. The methods typically comprise administering a pharmaceuticalcomposition of the present invention to an HCV patient, thereby reducingthe HCV viral level in the blood or liver of the patient. Anypharmaceutical composition described herein can be used in the methodsof the present invention.

In addition, the present invention features use of the compounds orsalts of the present invention for the manufacture of medicaments forthe treatment of HCV infection. Any compound described herein, or apharmaceutically acceptable salt thereof, can be used to makemedicaments of the present invention.

The foregoing description of the present invention provides illustrationand description, but is not intended to be exhaustive or to limit theinvention to the precise one disclosed. Modifications and variations arepossible in light of the above teachings or may be acquired frompractice of the invention. Thus, it is noted that the scope of theinvention is defined by the claims and their equivalents.

What is claimed is:
 1. A compound of Formula I, or a pharmaceuticallyacceptable salt thereof,

wherein: A₁ is C₅-C₁₀carbocyclyl or 5- to 10-membered heterocyclyl, andis substituted with —X₁—R₂, wherein said C₅-C₁₀-carbocyclyl and 5- to10-membered heterocycly are optionally substituted with one or moreR_(A); A₂ is C₅-C₁₀carbocyclyl or 5- to 10-membered heterocyclyl, and issubstituted with —X₂—R₈, wherein said C₅-C₁₀carbocyclyl and 5- to10-membered heterocyclyl are optionally substituted with one or moreR_(A); X₁ and X₂ are each independently selected from a bond, —L_(S)—,—O—, —S—, or —N(R_(B))—; R₇ and R₈ are each independently selected fromhydrogen, —L_(A), C₅-C₁₋carbocyclyl, or 5- to 10-membered heterocyclyl,wherein at each occurrence said C₅-C₁₀carbocyclyl and 5- to 10-memberedheterocyclyl are each independently optionally substituted with one ormore R_(A); Z₁ and Z₂ are each independently selected from a bond,—C(R_(C)R_(C′))—, —O—, —S—, or —N(R_(B))—; W₁, W₂, W₃, and W₄ are eachindependently selected from N or C(R_(D)), wherein R_(D) isindependently selected at each occurrence from hydrogen or R_(A); R₁ andR₂ are each independently selected from hydrogen or R_(A); R₃ and R₄ areeach independently selected from hydrogen or R_(A); or R₃ and R₄, takentogether with the carbon atoms to which they are attached, form aC₅-C₁₀carbocyclic or 5- to 10-membered heterocyclic ring, wherein saidC₅-C₁₀carbocyclic and 5- to 10-membered heterocyclic ring are optionallysubstituted with one or more R_(A); R₅ and R₆ are each independentlyselected from hydrogen or R_(A); or R₅ and R₆, taken together with thecarbon atoms to which they are attached, form a C₅-C₁₀carbocyclic or 5-to 10-membered heterocyclic ring, wherein said C₅-C₁₀carbocyclic and 5-to 10-membered heterocyclic ring are optionally substituted with one ormore R_(A); T is selected from a bond, —L_(S)—, —L_(S)—M—L_(S)—,—L_(S)—M—L_(S)—M′—L_(S)—, wherein M and M′ are each independentlyselected from a bond, —O—, —S—, —N(R_(B))—, —C(O)—, —S(O)₂—, —S(O)—,—OS(O)—, —OS(O)₂—, —S(O)₂O—, —S(O)O—, —C(O)O—, —OC(O)—, —OC(O)O—,—C(O)N(R_(B))—, —N(R_(B))C(O)—, —N(R_(B))C(O)O—, —OC(O)N(R_(B))—,—N(R_(B))S(O)—, —N(R_(B))S(O)₂, —S(O)N(R_(B)), —S(O)₂N(R_(B))—,—C(O)N(R_(B))C(O)—, —N(R_(B))C(O)N(R_(B′))—, —N(R_(B))SO₂N(R_(B′))—,—N(R_(B))S(O)N(R_(B′))—, C₅-C₁₀carbocycle, or 5- to 10-memberedheterocycle, and wherein R is optionally substituted with one or moreR_(A); R_(A) is independently selected at each occurrence from halogen,hydroxy, mercapto, amino, carboxy, nitro, phosphate, oxo, thioxo,formyl, cyano, —L_(A), or —L_(S)—R_(B); R_(B) and R_(B′) are eachindependently selected at each occurrence from hydrogen; or C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆carbocyclyl,C₃-C₆carbocyclylC₁-C₆alkyl, 3- to 6-membered heterocyclyl, or (3- or6-membered heterocyclyl)C₁-C₆alkyl, each of which is independentlyoptionally substituted at each occurrence with one or more substituentsselected from halogen, hydroxy, mercapto, amino, carboxy, nitro,phosphate, oxo, thioxo, formyl or cyano; R_(C) and R_(C′) are eachindependently selected at each occurrence from hydrogen; halogen;hydroxy; mercapto; amino; carboxy; nitro; phosphate; oxo; thioxo;formyl; cyano; or C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, orC₃-C₆carbocyclyl, each of which is independently optionally substitutedat each occurrence with one or more substituents selected from halogen,hydroxy, mercapto, amino, carboxy, nitro, phosphate, oxo, thioxo, formylor cyano; L_(A) is independently selected at each occurrence fromC₁-C₆alkyl, C₂-C₆alkenyl, or C₂-C₆alkynyl, each of which isindependently optionally substituted at each occurrence with one or moresubstituents selected from halogen, —O—R_(S), —S—R_(S), —N(R_(S)R_(S′)),—OC(O)R_(S), —C(O)OR_(S), nitro, phosphate, oxo, thioxo, formyl orcyano; L_(S), L_(S′) and L_(S″) are each independently selected at eachoccurrence from a bond; a C₁-C₆alkylene, C₂-C₆alkenylene, orC₂-C₆alkynylene, each of which is independently optionally substitutedat each occurrence with one or more substituents selected from halogen,—O—R_(S), —S—R_(S), —N(R_(S)R_(S′)), —OC(O)R_(S), —C(O)OR_(S), nitro,phosphate, oxo, thioxo, formyl or cyano; R_(E) is independently selectedat each occurrence from —O—R_(S), —S—R_(S), —C(O)R_(S), —OC(O)R_(S),—N(R_(S))C(O)N(R_(S′)R_(S″)), —N(R_(S))SO₂R_(S′), —SO₂N(R_(S)R₄₀),—N(R_(S))SO₂N(R_(S′R) _(S″)), —N(R_(S))S(O)N(R_(S′)R_(S″)),—OS(O)—R_(S), —OS(O)₂—R_(S), —S(O)₂OR_(S), —S(O)OR_(S), —OC(O)OR_(S),—N(R_(S))C(O)OR_(S′), —OC(O)N(R_(S)R_(S′), —N(R) _(S))S(O)—R_(S′),—S(O)N(R_(S)R_(S′)), —C(O)N(R_(S))C(O)—R_(S′), C₃-C₆-carbocyclyl, or 3-to 6-membered heterocyclyl, and said C₃-C₆carbocyclyl and 3- to6-membered heterocyclyl are each independently optionally substituted ateach occurrence with one or more substituents selected from R_(S)(except hydrogen), halogen, —O—R_(B), —S—R_(B), —N(R_(B)R_(B′)),—OC(O)R_(B), —C(O)OR_(B), nitro, phosphate, oxo, thioxo, formyl orcyano; and R_(S), R_(S′) and R_(S″) are each independently selected ateach occurrence from hydrogen; or C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₃-C₆carbocyclyl, C₃-C₆carbocyclylC₁-C₆alkyl, 3- to6-membered heterocyclyl, or (3- to 6-membered heterocyclyl)C₁-C₆alkyl,each of which is independently optionally substituted at each occurrencewith one or more substituents selected from halogen, —O—R_(B), —S—R_(B),—N(R_(B)R_(B′)), —OC(O)R_(B), —C(O)OR_(B), nitro, phosphate, oxo,thioxo, formyl or cyano.
 2. The compound or salt of claim 1, wherein: A₁is C₅-C₆carbocyclyl or 5- to 6-membered heterocyclyl, and is substitutedwith —X₁—R₇, wherein said C₅-C₆carbocyclyl and 5- to 6-memberedheterocyclyl are optionally substituted with one or more R_(A); A₂ isC₅-C₆carbocyclyl or 5- to 6-membered heterocyclyl, and is substitutedwith —X₂—R₈, wherein said C₅-C₆carbocyclyl and 5- to 6-memberedheterocyclyl are optionally substituted with one or more R_(A); R₃ andR₄ are each independently selected from hydrogen or R_(A); or R₃ and R₄,taken together with the carbon atoms to which they are attached, form aC₅-C₆carbocyclic or 5- to 6-membered heterocyclic ring, wherein saidC₅-C₆carbocyclic and 5- to 6-membered heterocyclic ring are optionallysubstituted with one or more R_(A); and R₅ and R₆ are each independentlyselected from hydrogen or R_(A); or R₅ and R₆, taken together with thecarbon atoms to which they are attached, form a C₅-C₆carbocyclic or 5-to 6-membered heterocyclic ring, wherein said C₅-C₆carbocyclic and 5- to6-membered heterocyclic ring are optionally substituted with one or moreR_(A).
 3. The compound or salt of claim 2, wherein at least one of R₇and R₈ is C₅-C₆carbocyclyl or 5- to 6-membered heterocyclyl, and isoptionally substituted with one or more R_(A).
 4. The compound or saltof claim 2, wherein said at least one of R₇ and R₈ is phenyl, and isoptionally substituted with one or more R_(A).
 5. The compound or saltof claim 2, wherein R₇ and R₈ are independently selected fromC₅-C₆carbocyclyl or 5- to 6-membered heterocyclyl, and at eachoccurrence said C₅-C₆carbocyclyl and 5- to 6-membered heterocyclyl areeach independently optionally substituted with one or more R_(A).
 6. Thecompound or salt of claim 2, wherein R₇ and R₈ are phenyl, and are eachindependently optionally substituted with one or more R_(A).
 7. Thecompound or salt of claim 2, wherein A₁ and A₂ are phenyl, and are eachindependently optionally substituted with one or more R_(A).
 8. Thecompound or salt of claim 1, wherein W₁, W₂, W₃ and W₄ are N, and Z₁ andZ₂ are independently —N(R_(B))—.
 9. The compound or salt of claim 1,wherein: R₃ and R₄ are each independently selected from hydrogen orR_(A); or R₃ and R₄, taken together with the carbon atoms to which theyare attached, form

R₅ and R₆ are each independently selected from hydrogen or R_(A); or R₅and R₆, taken together with the carbon atoms to which they are attached,form

R₉, R₁₀, R₁₁, R₁₂, R₃, and R₁₄ are each independently selected fromhydrogen or R_(A).
 10. The compound or salt of claim 9, wherein: W₁, W₂,W₃ and W₄ are N; Z₁ and Z₂ are independently —N(R_(B))—; and at leastone of X₁ and X₂ is —CH₂—, —O—, or —S—.
 11. The compound or salt ofclaim 9, wherein: W₁, W₂, W₃ and W₄ are N; Z₁ and Z₂ are —NH—; at leastone of X₁ and X₂ is —CH₂—, —O—, or —S—; at least one of R₇ and R₈ isphenyl, and is optionally substituted with one or more R_(A); R₁ and R₂are hydrogen; R₉, R₁₀, R₁₁, R₁₂, R₁₃, and R₁₄ are each independentlyselected from hydrogen; halogen; or C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₃-C₆carbocyclyl, or C₃-C₆carbocyclylC₁-C₆alkyl, each ofwhich is independently optionally substituted at each occurrence withone or more substituents selected from halogen, hydroxy, mercapto,amino, carboxy, nitro, phosphate, oxo, thioxo, formyl or cyano.
 12. Thecompound or salt of claim 9, wherein W₁, W₂, W₃ and W₄ are N; Z₁ and Z₂are —NH—; X₁ and X₂ are each independently selected from —CH₂—, —O—, or—S—; R₇ and R₈ are phenyl and are each independently optionallysubstituted with one or more R_(A); R₁ and R₂ are hydrogen; R₉, R₁₀,R₁₁, R₁₂, R₁₃, and R₁₄ are each independently selected from hydrogen,halogen; or C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆carbocyclyl, orC₃-C₆carbocyclyC₁-C₆alkyl, each of which is independently optionallysubstituted at each occurrence with one or more substituents selectedfrom halogen, hydroxy, mercapto, amino, carboxy, nitro, phosphate, oxo,thioxo, formyl or cyano.
 13. A compound of Formula II, or apharmaceutically acceptable salt thereof,

wherein: X₁ and X₂ are each independently selected from a bond, —L_(S)—,—O—, —S—, or —N(R_(B))—; R₇ and R₈ are each independently selected fromhydrogen, —L_(A), C₅-C₁₀carbocyclyl, or 5- to 10-membered heterocyclyl,wherein at each occurrence said C₅-C₁₀carbocyclyl and 5- to 10-memberedheterocyclyl are each independently optionally substituted with one ormore R_(A); Z₁ and Z₂ are each independently selected from a bond,—C(R_(C)R_(C′))—, —O—, —S—, or —N(R_(B))—; W₁, W₂, W₃, W₄, W₅, W₆, W₇,and W₈ are each independently selected from N or C(R_(D)), wherein R_(D)is independently selected at each occurrence from hydrogen or R_(A); R₁,R₂, R₉, R₁₁, R₁₂, R₁₄, R₁₅, and R₁₆ are each independently selected ateach occurrence from hydrogen or R_(A); m and n are each independentlyselected from 0, 1, 2, or 3; T is selected from a bond, —L_(S)—,—L_(S)—M—L_(S)—, —L_(S)—M—L_(S)—M′—L_(S′)—, wherein M and M′ are eachindependently selected from a bond, —O—, —S—, —N(R_(B)), —C(O)—,—S(O)₂—, —S(O)—, —OS(O)—, —OS(O)₂—, —S(O)₂O—, —S(O)O—, —C(O)O—, —OC(O)—,—OC(O)O—, —C(O)N(R_(B))—, —N(R_(B))C(O)—, —N(R_(B))C(O)O—,—OC(O)N(R_(B))—, —N(R_(B))S(O)—, —N(R_(B))S(O)₂—, —S(O)N(R_(B))—,—S(O)₂N(R_(B))—, —C(O)N(R_(B))C(O)—, —N(R_(B))C(O)N(R_(B′))—,—N(R_(B))SO₂N(R_(B′))—, —N(R_(B))S(O)N(R_(B′))—, C₅-C₁₀carbocycle, or 5-to 10-membered heterocycle, and wherein T is optionally substituted withone or more R_(A); R_(A) is independently selected at each occurrencefrom halogen, hydroxy, mercapto, amino, carboxy, nitro, phosphate, oxo,thioxo, formyl, cyano, —L_(A), or —L_(S)—R_(B); R_(B) and R_(B′) areeach independently selected at each occurrence from hydrogen; orC₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆carbocyclyl,C₃-C₆carbocyclylC₁-C₆alkyl, 3- to 6-membered heterocyclyl, or (3- or6-membered heterocyclyl)C₁-Calkyl, each of which is independentlyoptionally substituted at each occurrence with one or more substituentsselected from halogen, hydroxy, mercapto, amino, carboxy, nitro,phosphate, oxo, thioxo, formyl or cyano; R_(C) and R_(C′) are eachindependently selected at each occurrence from hydrogen; halogen;hydroxy; mercapto; amino; carboxy; nitro; phosphate; oxo; thioxo;formyl; cyano; or C₃-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, orC₃-C₆carbocyclyl, each of which is independently optionally substitutedat each occurrence with one or more substituents selected from halogen,hydroxy, mercapto, amino, carboxy, nitro, phosphate, oxo, thioxo, formylor cyano; L_(A) is independently selected at each occurrence fromC₁-C₆alkyl, C₂-C₆alkenyl, or C₂-C₆alkynyl, each of which isindependently optionally substituted at each occurrence with one or moresubstituents selected from halogen, —O—R_(S), —S—R_(S), —N(R_(S)R_(S′)),—OC(O)R_(S), —C(O)OR_(S), nitro, phosphate, oxo, thioxo, formyl orcyano; L_(S), L_(S′) and L_(S″) are each independently selected at eachoccurrence from a bond; or C₁-C₆alkylene, C₂-C₆alkenylene, orC₂-C₆alkynylene, each of which is independently optionally substitutedat each occurrence with one or more substituents selected from halogen,—O—R_(S), —S—R_(S), —N(R_(S)R_(S′)), —OC(O)R_(S), —C(O)OR_(S), nitro,phosphate, oxo, thioxo, formyl or cyano; R_(E) is independently selectedat each occurrence from —O—R_(S), —S—R_(S), —C(O)R_(S), —OC(O)R_(S),—C(O)OR_(S), —N(R_(S)R_(S′)), —S(O)R_(S), —SO₂R_(S),—C(O)N(R_(S)R_(S′)), —N(R_(S))C(O)R_(S′), —N(R_(S))C(O)N(R_(S′)R_(S″)),—OS(O)—R_(S), —OS(O)₂—R_(S), —S(O)₂OR_(S), —S(O)OR_(S), —OC(O)OR_(S),—N(R_(S))C(O)OR_(S′), —OC(O)N(R_(S)R_(S′)), —N(R_(S))S(O)—R_(S′),—(O)N(R_(S)R_(S′)), —C(O)N(R_(S))C(O)—R_(S′), C₃-C₆carbocyclyl, or 3- to6-membered heterocyclyl, and said C₃-C₆carbocyclyl and 3- to 6-memberedheterocyclyl are each independently optionally substituted at eachoccurrence with one or more substituents selected from R_(S) (excepthydrogen), halogen, —O—R_(B), —S—R_(B), —N(R_(B)R_(B′)), —OC(O)R_(B),—C(O)OR_(B), nitro, phosphate, oxo, thioxo, formyl or cyano; and R_(S),R_(S′) and R_(S″) are each independently selected at each occurrencefrom hydrogen; or C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₃-C₆carbocyclyl, C₃-C₆carbocyclylC₁-C₆alkyl, 3- to 6-memberedheterocyclyl, or (3- to 6-membered heterocyclyl)C₁-C₆alkyl, each ofwhich is independently optionally substituted at each occurrence withone or more substituents selected from halogen, —O—R_(B), —S—R_(B),—N(R_(B)R_(B′)), —OC(O)R_(B), —C(O)OR_(B), nitro, phosphate, oxo,thioxo, formyl or cyano.
 14. The compound or salt of claim 13, wherein:at least one of X₁ and X₂ is selected from —CH₂—, —O—, or —S—; at leastone of R₇ and R₈ is selected from C₃-C₆carbocyclyl or 5- to 6-memberedheterocyclyl, wherein said C₅-C₆carbocyclyl and 5- to 6-memberedheterocyclyl are optionally substituted with one or more R_(A); and Z₁and Z₂ are each independently —N(R_(B))—.
 15. The compound or salt ofclaim 14, wherein: X₁ and X₂ are each independently selected from —CH₂—,—O—, or —S—; R₇ and R₈ are each independently selected fromC₅-C₆carbocyclyl or 5- to 6-membered heterocyclyl, wherein at eachoccurrence said C₅-C₆carbocyclyl and 5- to 6-membered heterocyclyl areeach optionally substituted with one or more R_(A); and Z₁ and Z₂ areeach independently —N(R_(B))—.
 16. The compound or salt of claim 13,wherein: W₁, W₂, W₃, W₄, W₅, and W₇ are N, and W₆ and W₈ are eachindependently C(R_(D)); R₁ and R₂ are hydrogen; R₇ and R₈ are phenyl,and are each independently optionally substituted with one or moreR_(A); and R₉, R₁₁, R₁₂, R₁₄, and R_(D) are each independently selectedat each occurrence from hydrogen; halogen; or C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₃-C₆carboxycyclyl, or C₃-C₆carbocyclylC₁-C₆alkyl, each ofwhich is independently optionally substituted at each occurrence withone or more substituents selected from halogen, hydroxy, mercapto,amino, carboxy, nitro, phosphate, oxo, thioxo, formyl or cyano.
 17. Acompound of Formula III, or a pharmaceutically acceptable salt thereof,

wherein: X₁ and X₂ are each independently selected from a bond, —L_(S)—,—O—, —S—, or —N(R_(B))—; R₇ and R₈ are each independently selected fromhydrogen, —L_(A), C₅-C₁₀carbocyclyl, or 5- to 10-membered heterocyclyl,wherein at each occurrence said C₅-C₁₀carbocyclyl and 5- to 10-memberedheterocyclyl are each independently optionally substituted with one ormore R_(A); Z₁ and Z₂ are each independently selected from a bond,—C(R_(C)R_(C′))—, —O—, —S—, or —N(R_(B))—; W₁, W₂, W₃, W₄, W₅, W₆, W₇,and W₈ are each independently selected from N or C(R_(D)), wherein R_(D)is independently selected at each occurrence from hydrogen or R_(A); R₁,R₂, R₉, R₁₁, R₁₂, R₁₄, R₁₅, and R₁₆ are each independently selected ateach occurrence from hydrogen or R_(A); m and n are each independentlyselected from 0, 1, 2, or 3; T is selected from a bond, —L_(S)—,—L_(S)—M—L_(S′)—, —L_(S)—M—L_(S)—M′—L_(S″)—, wherein M and M′ are eachindependently selected from a bond, —O—, —S—, —N(R_(B))—, —C(O)—,—S(O)₂—, —S(O)—, —OS(O)—, —OS(O)₂—, —S(O)₂O—, —S(O)O—, —C(O)O—, —OC(O)—,—OC(O)O—, —C(O)N(R_(B))—, —N(R_(B))C(O)—, —N(R_(B))C(O)O—,—OC(O)N(R_(B))—, N(R_(B))S(O)—, —N(R_(B))S(O)₂—, —S(O)N(R_(B))—,—S(O)₂N(R_(B))—, —C(O)N(R_(B))C(O)—, —N(R_(B))C(O)N(R_(B′))—,—N(R_(B))SO₂N(R_(B′))—, —N(R_(B))S(O)N(R_(B′))—, C₅-C₁₀carbocycle, or 5-to 10-membered heterocycle, and wherein T is optionally substituted withone or more R_(A); R_(A) is independently selected at each occurrencefrom halogen, hydroxy, mercapto, amino, carboxy, nitro, phosphate, oxo,thioxo, formyl, cyano, —L_(A), or —L_(S)—R_(E); R_(B) and R_(B′) areeach independently selected at each occurrence from hydrogen; orC₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆carbocyclyl,C₃-C₆carbocyclylC₁-C₆alkyl, 3- to 6-membered heterocyclyl, or (3- or6-membered heterocyclyl)C₁-C₆alkyl, each of which is independentlyoptionally substituted at each occurrence with one or more substituentsselected from halogen, hydroxy, mercapto, amino, carboxy, nitro,phosphate, oxo, thioxo, formyl or cyano; R_(C) and R_(C′) are eachindependently selected at each occurrence from hydrogen; halogen;hydroxy; mercapto; amino; carboxy; nitro; phosphate; oxo; thioxo;formyl; cyano; or C₃-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, orC₃-C₆carbocyclyl, each of which is independently optionally substitutedat each occurrence with one or more substituents selected from halogen,hydroxy, mercapto, amino, carboxy, nitro, phosphate, oxo, thioxo, formylor cyano; L_(A) is independently selected at each occurrence fromC₁-C₆alkyl, C₂-C₆alkenyl, or C₂-C₆alkynyl, each of which isindependently optionally substituted at each occurrence with one or moresubstituents selected from halogen, —O—R_(S), —S—R_(S), —N(R_(S)R_(S′)),—OC(O)R_(S), —C(O)OR_(S), nitro, phosphate, oxo, thioxo, formyl orcyano; L_(S), L_(S′) and L_(S″) are each independently selected at eachoccurrence from a bond; or C₁-C₆alkylene, C₂-C₆alkenylene, orC₂-C₆alkynylene, each of which is independently optionally substitutedat each occurrence with one or more substituents selected from halogen,—O—R_(S), —S—R_(S), —N(R_(S)R_(S′)), —OC(O)R_(S), —C(O)OR_(S), nitro,phosphate, oxo, thioxo, formyl or cyano; R_(E) is independently selectedat each occurrence from —O—R_(S), —S—R_(S), —C(O)R_(S), —OC(O)R_(S),—C(O)OR_(S), —N(R_(S)R_(S′)), —S(O)R_(S), —SO₂R_(S),—C(O)N(R_(S)R_(S′)), —N(R_(S))C(O)R_(S′), —N(R_(S))C(O)N(R_(S′R) _(S″)),—N(R_(S))SO₂R_(S′), —SO₂N(R_(S)R_(′)), —N(R₈)SO₂N(R_(S′)R_(S″)),—N(R_(S))S(O)N(R_(S′)R_(S″)), —OS(O)—R_(S), —OS(O)₂—R_(S), —S(O)₂OR_(S),—S(O)OR_(S), —OC(O)OR_(S), —N(R_(S))C(O)OR_(S′), —OC(O)N(R_(S)R_(S′)),—N(R_(S))S(O)—R_(S′), —S(O)N(R_(S)R_(S′)), —C(O)N(R_(S))C(O)—R_(S′),C₃-C₆carbocyclyl, or 3- to 6-membered heterocyclyl, and saidC₃-C₆carbocyclyl and 3- to 6-membered heterocyclyl are eachindependently optionally substituted at each occurrence with one or moresubstituents selected from R_(S) (except hydrogen), halogen, —O—R_(B),—S—R_(B), —N(R_(B)R_(B′)), —OC(O)R_(B), —C(O)OR_(B), nitro, phosphate,oxo, thioxo, formyl or cyano; and R_(S), R_(S′) and R_(S″) are eachindependently selected at each occurrence from hydrogen; or C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆carbocyclyl,C₃-C₆carbocyclylC₁-C₆alkyl, 3- to 6-membered heterocyclyl, or (3- to6-membered heterocyclyl)C₁-C₆alkyl, each of which is independentlyoptionally substituted at each occurrence with one or more substituentsselected from halogen, —O—R_(B), —S—R_(B), —N(R_(B)R_(B′)), —OC(O)R_(B),—C(O)OR_(B), nitro, phosphate, oxo, thioxo, formyl or cyano.
 18. Thecompound or salt of claim 17, wherein: at least one of X₁ and X₂ isselected from —CH₂—, —O—, or —S—; at least one of R₇ and R₈ is selectedfrom C₅C₆carbocyclyl or 5- to 6-membered heterocyclyl, wherein saidC₅-C₆carbocyclyl and 5- to 6-membered heterocyclyl are optionallysubstituted with one or more R_(A); and Z₁ and Z₂ are each independently—N(R_(B))—.
 19. The compound or salt of claim 17, wherein X₁ and X₂ areeach independently selected from —CH₂—, —O—, or —S—; R₇ and R₈ are eachindependently selected from C₅-C₆carbocyclyl or 5- to 6-memberedheterocyclyl, wherein at each occurrence said C₅-C₆carbocyclyl and 5- to6-membered heterocyclyl are each optionally substituted with one or moreR_(A); and Z₁ and Z₂ are each independently —N(R_(B))—.
 20. The compoundor salt of claim 17, wherein: W₁, W₂, W₃, W₄, W₅, and W₇ are N, and W₆and W₈ are each independently C(R_(D)); R₁ and R₂ are hydrogen; R₇ andR₈ are phenyl, and are each independently optionally substituted withone or more R_(A); and R₉, R₁₁, R₁₂, R₁₄, and R_(D) are eachindependently selected at each occurrence from hydrogen; halogen; orC₂-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆carbocyclyl, orC₃-C₆carbocyclyC₁-C₆alkyl, each of which is independently optionallysubstituted at each occurrence with one or more substituents selectedfrom halogen, hydroxy, mercapto, amino, carboxy, nitro, phosphate, oxo,thioxo, formyl or cyano.
 21. A pharmaceutical composition comprising acompound or salt of claim
 1. 22. A method of inhibiting HCV virusreplication, comprising contacting cells infected with HCV virus with acompound or salt of claim
 1. 23. A method of treating HCV infection,comprising administering to an HCV patient a compound or salt ofclaim
 1. 24. A process of making a compound of claim 1, comprising astep described in one of schemes described herein.